Substituted furanopyrimidine compounds as pde1 inhibitors

ABSTRACT

Substituted furanopyrimidine chemical entities of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R a  has any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive therapies; modulating and treating disorders mediated by PDE1 activity or dopaminergic signaling; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent losses of function; treating stroke, including cognitive and motor deficits during stroke rehabilitation; facilitating neuroprotection and neurorecovery; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including cardiovascular, renal, hematological, gastroenterological, liver, cancer, fertility, and metabolic disorders.

BACKGROUND Field

The present invention relates to certain substituted furanopyrimidinecompounds and related chemical entities; compositions containing them;processes for making them; and their use in various methods andtherapies, including the enhancement of neuroplasticity, and thetreatment of neurological, cognitive, cardiovascular, gastrointestinal,renal disorders, and other conditions and diseases involving PDE1,dopaminergic, or cyclic nucleotide signaling.

Description of the Related Technology

The cyclic nucleotides, adenosine and guanosine 3′,5′-cyclicmonophosphate (cAMP and cGMP) are second messengers in cellularsignaling cascades activated by diverse transduction pathways, such asthose triggered by neurotransmitters and hormones. See, e.g., Kelly andBrandon, 2009, Prog. Brain Res. 179, 67-73; Schmidt, 2010, Curr. Top.Med. Chem. 10, 222-230. Once generated, cAMP and cGMP transmit theirsignals through various tertiary effectors, such as cAMP dependentprotein kinase (PKA), cGMP dependent protein kinase (PKG), and otherproteins. In turn, these effectors modulate additional targets indownstream cascades, such as enzymes and transcription factors,ultimately resulting in cellular changes that impact numerousphysiological processes, including neuronal plasticity and survival,muscle contraction, sensory transduction, cell division, stressresponse, and inflammation.

Cyclic nucleotide levels are subject to tight regulatory controls,including the action of phosphodiesterases (PDEs), a superfamily ofintracellular enzymes that hydrolyze cAMP and cGMP to their inactivenon-cyclic forms, 5′-AMP and 5′-GMP. See, e.g., Bender and Beavo, 2006,Pharmacol. Rev. 58, 488-520. Mammalian PDEs can be divided into 11families, PDE1-11, based on structural, biochemical, and pharmacologicalproperties. Some are cAMP-selective hydrolases (PDE4, 7, and 8), someare cGMP-selective hydrolases (PDE5, 6, and 9), and some hydrolyze bothcAMP and cGMP (PDE1, 2, 3, 10, and 11). By regulating cAMP and cGMPlevels, PDEs play a key role in modulating cyclic nucleotide cascades,and they have become desirable targets for treating various diseases anddisorders due to their different tissue distribution and functionalproperties. See, e.g., Keravis and Lugnier, 2001, Br. J. Pharmacol. 165,1288-1305. Alterations in cyclic nucleotide concentrations, for example,can impact biochemical and physiological process linked to cognitivefunction (Kelly and Brandon, 2009, Prog. Brain Res. 179, 67-73; Schmidt,2010, Curr. Top. Med. Chem. 10, 222-230; Perez-Gonzalez et al., 2013,Neurobiol. Aging. 34, 2133-2145; Lipina et al., 2013, Neuropharmacology64, 295-214; Morales-Garcia et al., 2016, Stem Cells. 35, 458-472).

The PDE1 family, which hydrolyzes both cAMP and cGMP, is distinguishedfrom other PDEs by requiring calcium (Ca²⁺) and calmodulin (CaM) forfull activation (Goraya and Cooper, 2005, Cell. Signal. 17, 789-797).The binding of Ca²⁺-CaM complexes at sites near the N-terminus of PDE1stimulates hydrolysis of cyclic nucleotides. In intact cells, PDE1 isalmost exclusively activated by Ca²⁺ entering the cell from theextracellular space. PDE1 is therefore a point of convergence andintegration for multiple signaling pathways that regulate numerousdownstream targets and cellular events. For review, see Bender andBeavo, 2006, Pharmacol. Rev. 58, 488-520; Sharma et al., 2006, Int. J.Mol. Med. 18, 95-105.

The PDE1 family comprises three members, encoded by separate genes(pde1a, pde1b, and pde1c) that give rise to multiple isoforms viaalternative splicing and differential transcription. All PDE1 enzymesappear to hydrolyze both cAMP and cGMP, although they can differ intheir relative affinities for each, as well as their relative affinitiesfor calcium and CaM. For review, see Bender and Beavo, 2006, Pharmacol.Rev. 58, 488-520. PDE1 isoforms show distinct but overlapping patternsof expression throughout the body. In the brain, PDE1 is expressed innumerous regions, including the striatum, cerebral cortex, frontal lobe,hippocampus, cerebellum, and amygdala. Brain expression patterns ofPDE1B correlate closely with that of dopamine receptors, implicatingPDE1 in the modulation of dopamine signaling, a role supported byexperiments in PDE1B knockout mice (Reed et al., 2002, J. Neurosci. 22,5188-5197). Outside the brain, PDE1 is expressed in numerous areas,including muscle, heart, kidney, pancreas, lungs, stomach, and liver. Inthe cardiovascular system, PDE1 appears to play a central role inorganizing cAMP microdomains and mediating hormonal specificity incardiac cells. See Maurice et al., 2003, Mol. Pharm. 64, 533-546.

Such properties implicate PDE1 in numerous physiological andpathological processes. Alterations in cyclic nucleotide signalingpathways, including those involving PDE1, are implicated in variousdisorders of the brain, such as depression, schizophrenia and cognitivedisorders. See, e.g., Keravis and Lugnier, 2012, Br. J. Pharmacol. 165,1288-1305. Inhibiting PDE1 activity in the nervous system, for example,can increase cAMP or cGMP levels and consequently induce expression ofneuronal plasticity-related genes, neurotrophic factors, andneuroprotective molecules. Similarly, PDE1 enzymes and cyclicnucleotides have been implicated in the etiology of vascular disorders,such as hypertension, myocardial infarction, and heart failure, as wellas the development and progression of renal disease. See, e.g., Milleret al., 2011, Basic Res. Cardiol. 106, 1023-1039; Miller et al, 2009,Circ. Res. 105, 956-964; Wang et al., 2010, Kidney Int. 77. 129-140;Cheng et al., 2007, Soc. Exp. Biol. Med. 232, 38-51; Dousa, 1999, KidneyInt. 55, 29-62.

These and other studies highlight the interest in PDE1 as a target fortreating numerous disorders and modulating physiological processes, suchas cognition. There is a substantial need for PDE1 inhibitors withdesirable pharmacological and therapeutic properties, such as effectivepotency, exposure, selectivity, and safety. The present inventionaddresses these and other needs in the art by disclosing substitutedfuranopyrimidine chemical entities as potent, selective, andwell-tolerated PDE1 inhibitors.

SUMMARY

The present disclosure relates to substituted furanopyrimidine chemicalentities; compositions including such entities; processes for makingthem; and their use in various methods, including the treatment ofneurological and peripheral disorders associated with PDE1, as disclosedherein.

Some embodiments provide a chemical entity of Formula (I), and morespecifically, a compound, or pharmaceutically acceptable salt of acompound of Formula (I):

wherein R^(a) has any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ia), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Ia):

wherein L¹ and L³ have any of the values described herein

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ib), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Ib):

wherein L¹, L², and L³ have any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Iba), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Iba):

wherein L², L³, m and R^(b) have any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ibb), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Ibb):

wherein L², L³, m, R^(d) and R^(b) have any of the values describedherein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ic), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Ic):

wherein L⁴ and L⁵ have any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icaa) or (Icab), or more specifically, a compound ora pharmaceutically acceptable salt of a compound of Formula (Icaa) or(Icab):

wherein L⁶, B¹, B², and p have any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icb), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Icb):

wherein L⁶, B², Q, and q have any of the values described herein.

In some embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icc), or more specifically, a compound or apharmaceutically acceptable salt of a compound of Formula (Icc):

wherein L⁶, B¹, D¹, E, G,and r have any of the values described herein.

In some embodiments, the chemical entity is selected from any of thespecies described or exemplified herein, and more particularly, is acompound, or pharmaceutically acceptable salt thereof.

In some embodiments, the chemical entities, and compositions includingsuch entities, are used in a wide range of methods, as described herein.In some embodiments, the methods include metabolic and reaction kineticstudies, detection and imaging techniques, and radioactive treatments.In some embodiments, the methods include inhibiting PDE1, treatingdisorders that are mediated by PDE1, treating disorders characterized byalterations in dopamine signaling, enhancing neuronal plasticity,conferring neuroprotection, and promoting neurogenesis. In someembodiments, the methods include treating neurological disorders,particularly CNS disorders, and more particularly, mental andpsychiatric disorders, cognitive disorders, movement disorders, andneurodegenerative disorders. In some embodiments, the methods aredirected to treating peripheral disorders, including cardiovascular,renal, hematological, gastrointestinal, liver, fertility, cancer, andmetabolic disorders.

In some embodiments, the chemical entities, and compositions includingsuch entities, are useful as augmenting agents to increase theefficiency of cognitive and motor training, including training duringpost-stroke rehabilitation or post-traumatic brain injury (TBI)rehabilitation; and to increase the efficiency of non-human animaltraining protocols.

The disclosure is further directed to the general and specificembodiments defined, respectively, and by the independent and dependentclaims appended hereto, which are incorporated by reference herein.Additional embodiments, features, and advantages of the disclosure willbe apparent from the following detailed description and through practiceof the exemplary embodiments.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

Terms and Definitions

The use of headings and subheadings provided in the sections of thisspecification is solely for convenience of reference and does not limitthe various embodiments herein, which are to be construed by referenceto the specification as a whole.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value. Toprovide a more concise description, some of the quantitative expressionsgiven herein are not qualified with the term “about.” It is understoodthat, whether the term “about” is used explicitly or not, every quantitygiven herein is meant to refer to both the actual given value and theapproximation of such given value that would reasonably be inferredbased on the ordinary skill in the art, including equivalents andapproximations due to the experimental and/or measurement conditions forsuch given value. Accordingly, for any embodiment of the invention inwhich a numerical value is prefaced by “about” or “approximately”, thedisclosure includes an embodiment in which the exact value is recited.Conversely, for any embodiment of the invention in which a numericalvalue is not prefaced by “about” or “approximately”, the disclosureincludes an embodiment in which the value is prefaced by “about” or“approximately”.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

Furthermore, although items, elements or components of the embodimentsmay be described or claimed in the singular, the plural is contemplatedto be within the scope thereof, unless limitation to the singular isexplicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended, as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “normal,” “known” and terms ofsimilar meaning should not be construed as limiting the item describedto a given time period or to an item available as of a given time, butinstead should be read to encompass conventional, or normal technologiesthat may be available or known now or at any time in the future.Likewise, where this document refers to technologies that would beapparent or known to one of ordinary skill in the art, such technologiesencompass those apparent or known to the skilled artisan now or at anytime in the future.

As will become apparent to one of ordinary skill in the art afterreading this document, the illustrated embodiments and their variousalternatives may be implemented without confinement to the illustratedexamples.

Chemical Terms

The term “alkyl” refers to a fully saturated aliphatic hydrocarbon group(i.e., contains no double or triple bonds). The alkyl moiety may be astraight- or branched-chain alkyl group having from 1 to 12 carbon atomsin the chain, and more particularly, has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 carbons in the chain. Preferably, the alkyl moiety is-C₁₋₆alkyl, and more preferably is C₁₋₄alkyl. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “——”), ethyl (Et), n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl,isopentyl, tert-pentyl, hexyl, and isohexyl. Alkyl groups may beoptionally substituted with one or more substituents including, but notlimited to, hydroxyl, alkoxy, thioalkoxy, amino, aminoalkyl, and cyano.

The term “alkenyl” refers to unsaturated acyclic aliphatic moietieshaving at least one carbon-carbon double bond. The term alkenyl includesall possible geometric isomers including E and Z isomers of said alkenylmoiety unless specifically indicated. Examples of alkenyl radicalsinclude ethenyl, propenyl, butenyl, 1,4-butadienyl, and the like.

The term “alkynyl” refers to optionally substituted unsaturated acyclicaliphatic moieties having at least one carbon-carbon triple bond.Examples of alkynyl radicals include ethynyl, propynyl, butynyl and thelike.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain substituting one or morehydrogens with halogens. Examples of haloalkyl groups include, but arenot limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂Cl, and —CH₂CF₂CF₃.

The term “alkoxy” includes a straight chain or branched alkyl group withan oxygen atom linking the alkyl group to the rest of the molecule.Examples of alkoxy groups include, but are not limited to, methoxy,ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, and pentoxy.“Aminoalkyl,” “thioalkyl,” and “sulfonylalkyl” are analogous to alkoxy,replacing the terminal oxygen atom of alkoxy with, respectively, NH (orNR), S, and SO₂ where R is selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, phenyl, 5-, 6-, 9-, or10-membered heteroaryl, and 5-10 membered heterocycloalkyl, as definedherein.

The term “haloalkoxy” refers to alkoxy groups substituting one or morehydrogens with halogens. Examples of haloalkoxy groups include, but arenot limited to, -OCF₃, —OCHF₂, —OCH₂F, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂Cl,—OCH₂CF₂CF₃, and —OCH(CH₃)CHF₂.

The term “amino group” refers to an —NH₂ group.

The term “cyano” refers to the group —CN.

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon), having from 3 to 15 ring atoms per ring (carbon atoms in arylgroups are sp² hybridized). Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “phenyl” represents the following moiety:

The term “aryloxy” refers to a group having the formula, —O—R, wherein Ris an aryl group.

The term “cycloalkyl” refers to a fully saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 15 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is fully saturated or partially saturatedand includes at least one heteroatom selected from nitrogen, oxygen, andsulfur in the ring backbone. A heterocycloalkyl may have any degree ofsaturation provided that at least one ring in a polycyclic ringstructure is not aromatic. The heteroatom(s) may be present in either anon-aromatic or aromatic ring in the polycyclic structure. Theheterocycloalkyl group may have 3 to 20 ring members (i.e., the numberof atoms making up the ring backbone, including carbon atoms andheteroatoms), although the present definition also covers the occurrenceof the term “heterocycloalkyl” where no numerical range is designated.The heterocycloalkyl group may be designated as “3-15-memberedheterocycloalkyl,” “4-10-membered heterocycloalkyl,” “3-15-memberedC₂-₁₄heterocycloalkyl,” “5-9-membered C₄₋₈heterocycloalkyl,”“5-10-membered C₄-₉heterocycloalkyl,” “5-membered C₃₋₄heterocycloalkyl,”“6-membered C₄-₅heterocycloalkyl,” “7-membered C₅₋₆heterocycloalkyl,”“bicyclic or tricyclic 9-15-membered C₈₋₁₄heterocycloalkyl,” “monocyclicor bicyclic 3-10-membered C₂₋₉heterocycloalkyl,” “bicyclic 8-10-memberedC₄₋₉heterocycloalkyl,” “bicyclic 8-10-membered C₅₋₉heterocycloalkyl,”“monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl,” “monocyclic5-6-membered C₃₋₅₋heterocycloalkyl,” or similar designations. Theheterocycloalkyl may be a 5-10 membered ring or ring system comprisingone to four heteroatoms each independently selected from nitrogen,oxygen, and sulfur. The heterocycloalkyl may be a monocyclicfive-membered ring comprising one to three heteroatoms eachindependently selected from nitrogen, oxygen, and sulfur. Theheterocycloalkyl may be a monocyclic six-membered ring comprising one tothree heteroatoms each independently selected from nitrogen, oxygen, andsulfur. The heterocycloalkyl may be a bicyclic nine-membered ringcomprising one to three heteroatoms each independently selected fromnitrogen, oxygen, and sulfur. The heterocycloalkyl may be a bicyclicten-membered ring comprising one to three heteroatoms each independentlyselected from nitrogen, oxygen, and sulfur. The heterocycloalkyl may beoptionally substituted. Illustrative unsubstituted heterocycloalkylentities, in the form of properly bonded moieties, include:

Illustrative carbon or sulfur oxo-substituted heterocycloalkyl entities,in the form of properly bonded moieties, include:

The term “heteroaryl” refers to an aromatic monocyclic, fused bicyclic,or fused polycyclic ring or ring system having one or more heteroatomsselected from nitrogen, oxygen, and sulfur in the ring backbone. Whenthe heteroaryl is a ring system each ring in the ring system is fullyunsaturated. The heteroaryl group may have 5-18 ring members (i.e., thenumber of atoms making up the ring backbone, including carbon atoms andheteroatoms), although the present definition also covers the occurrenceof the term “heteroaryl” where no numerical range is designated. In someembodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7ring members. The heteroaryl group may be designated as “5-9-memberedheteroaryl,” “5-10-membered heteroaryl,” “5-9-membered C₄₋₈heteroaryl,”“5-10-membered C₄₋₉heteroaryl,” “5-6-membered C₃₋₅heteroaryl,”“6-membered C₄₋₅heteroaryl,” “5-membered C₃₋₄heteroaryl,” or similardesignations. The heteroaryl may be a 5-10 membered ring or ring systemcomprising one to four heteroatoms each independently selected fromnitrogen, oxygen, and sulfur. The heteroaryl may be a monocyclicfive-membered ring comprising one to four heteroatoms each independentlyselected from nitrogen, oxygen, and sulfur. The heteroaryl may be amonocyclic six-membered ring comprising one to four heteroatoms eachindependently selected from nitrogen, oxygen, and sulfur. The heteroarylmay be a bicyclic nine-membered ring comprising one to four heteroatomseach independently selected from nitrogen, oxygen, and sulfur. Theheteroaryl may be a bicyclic ten-membered ring comprising one to fourheteroatoms each independently selected from nitrogen, oxygen, andsulfur. In some embodiments, the heteroaryl may be a tautomer of aheterocycloalkyl where the heteroaryl is the predominate form underequilibrium conditions. Illustrative examples of heteroaryl groupsinclude the following entities, in the form of properly bonded moieties:

A “cycloalkoxy” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is fully saturated or partially saturatedhaving at least two carbons and at least one oxygen in the ringbackbone. A cycloalkoxy may have any degree of saturation provided thatat least one ring in a polycyclic ring structure is not aromatic. Theoxygen may be present in the non-aromatic or aromatic ring in thepolycyclic structure. The cycloalkoxy group may have 3 to 20 ringmembers (i.e., the number of atoms making up the ring backbone,including carbon atoms and heteroatoms), although the present definitionalso covers the occurrence of the term “cycloalkoxy” where no numericalrange is designated. The cycloalkoxy group may be designated as “3-15membered cycloalkoxy,” “4-10 membered cycloalkoxy,” “3-15 memberedC₂₋₁₄cycloalkoxy,” “5-9 membered C₄₋₈cycloalkoxy,” “5-10 memberedC₄-₉cycloalkoxy,” “5-membered C₃₋₄cycloalkoxy,” “6-memberedC₄₋₅cycloalkoxy,” “7-membered C₅₋₆cycloalkoxy,” or similar designations.The cycloalkoxy may be a 5-10 membered ring or ring system comprisingone oxygen and the remainder carbon in the ring backbone. Thecycloalkoxy may be optionally substituted. Illustrative unsubstitutedcycloalkoxy entities, in the form of properly bonded moieties, include:

Those skilled in the art will recognize that the species of aryl,cycloalkyl, heterocycloalkyl, and heteroaryl groups listed orillustrated above are not exhaustive, and that additional species withinthe scope of these defined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur), or N (nitrogen).

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesor circumstances where it does not. For example, “optionally substitutedalkyl” encompasses both “unsubstituted alkyl” and “substituted alkyl” asdefined below. It will be understood by those skilled in the art, withrespect to any group containing one or more substituents, that suchgroups are not intended to introduce any substitution or substitutionpatterns that are sterically impractical, synthetically non-feasibleand/or inherently unstable.

The term “substituted” means that the specified group or moiety bearsone or more substituents. A substituted group is derived from theunsubstituted parent group in which there has been an exchange of one ormore hydrogen atoms for another atom or group or derived from theunsubstituted parent group in which there has been an addition of one ormore atoms or group to a carbon, nitrogen or sulfur. Where the term“substituted” is used to describe a structural system, unless specifiedotherwise, the substitution is meant to occur at any valency-allowedposition on the system. The term “unsubstituted” means that thespecified group bears no substituents.

For simplicity, groups described herein that are capable of more thanone point of attachment (i.e., divalent, trivalent, polyvalent) may bereferred to with a common term. For example, the term “C₃₋₁₀cycloalkyl”can be used to describe a three to ten membered cycloalkyl group (L³)that is monovalent, as in -L¹-L³, wherein L³ has one point ofattachment, and that can also be divalent (L²), as in -L¹-L²-L³, whereinL² has two points of attachment.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), C₃-C₇-cycloalkyl-C₁-C₆-alkyl (optionally substitutedwith halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy), 3-10 membered heterocycloalkyl (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),3-10 membered heterocycloalkyl-C₁-C₆-alkyl (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),aryl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), 5-10 membered heteroaryl (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),5-10 membered heteroaryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo,cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether),aryloxy (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), C₃-C₇ cycloalkoxy (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), 3-10 membered heterocycloalkyl-oxy (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), 5-10 membered heteroaryl-oxy (optionally substitutedwith halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy), C₃-C₇-cycloalkyl-C₁-C₆-alkoxy (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),3-10 membered heterocycloalkyl-C₁-C₆-alkoxy (optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),aryl(C₁-C₆)alkoxy (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkoxy (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), sulfhydryl(mercapto), halo(C₁-C₆)alkyl (e.g., —CF₃), halo(C₁-C₆)alkoxy (e.g.,-OCF₃), C₁-C₆ alkylthio, arylthio (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),amino, amino(C₁-C₆)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato,isothiocyanato, sulfinyl, sulfonyl, and oxo (═O). Wherever a group isdescribed as “optionally substituted” that group can be substituted withthe above substituents unless the optional substituents are otherwisespecifically identified.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

As used herein, “tautomer” refers to the migration of protons betweenadjacent single and double bonds. The tautomerization process isreversible. Compounds described herein can undergo any possibletautomerization that is within the physical characteristics of thecompound. The following is an example tautomerization that can occur incompounds described herein:

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Where compounds described herein exist in various tautomeric forms, theterm “compound” is intended to include all tautomeric forms (tautomers)of the compound.

The term “chiral” refers to molecules, which have the property ofnon-superimposability of the mirror image partner.

“Stereoisomers” are compounds, which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space.

A “diastereomer” is a stereoisomer with two or more centers of chiralityand whose molecules are not mirror images of one another. Diastereomershave different physical properties, e.g., melting points, boilingpoints, spectral properties, and reactivities. Mixtures of diastereomersmay separate under high resolution analytical procedures such aselectrophoresis, crystallization in the presence of a resolving agent,or chromatography, using, for example a chiral HPLC column.

“Enantiomers” refer to two stereoisomers of a compound, which arenon-superimposable mirror images of one another. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and 1 or (+) and (-) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (-) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory.

A “racemic mixture” or “racemate” is an equimolar (or 50:50) mixture oftwo enantiomeric species, devoid of optical activity. A racemic mixturemay occur where there has been no stereoselection or stereospecificityin a chemical reaction or process.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

Chemical Entities

As used herein, the term “chemical entity” collectively refers to acompound, along with all pharmaceutically acceptable forms thereof,including pharmaceutically acceptable salts, chelates, solvates,conformers, crystalline forms/polymorphs, tautomers, prodrugs,metabolites, and mixtures thereof. In some embodiments, the chemicalentity is selected from the group consisting of a compound andpharmaceutically acceptable salts thereof.

Chelates

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points.

Solvates

Additionally, any formula given herein is intended to refer also tosolvates, including hydrates, of compounds herein, and mixtures thereof,even if such forms are not listed explicitly. Some embodiments provide asolvate of a compound of Formula (I), and the use of such solvates inmethods described herein. Certain compounds of Formula (I) orpharmaceutically acceptable salts of compounds of Formula (I) may beobtained as solvates. In some embodiments, the solvent is water and thesolvates are hydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such asmethanol, methyl t-butyl ether, ethyl acetate, methyl acetate,(S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and thelike. Hydrates include a molecule of a compound associated with watermolecules.

Conformers and Crystalline Forms/Polymorphs

Some embodiments provide conformer and crystalline forms of a compoundof Formula (I), and their use in methods of the present disclosure. Aconformer is a structure that is a conformational isomer.

Conformational isomerism is the phenomenon of molecules with the samestructural formula but different conformations (conformers) of atomsabout a rotating bond.

Polymorphs refer to a solid material that can exist in more than oneform or crystal structure, where each form or crystal structure isdifferent from the other form(s) or crystal structure(s). Therefore, asingle compound may give rise to a variety of polymorphic forms havingdifferent and distinct physical properties, such as solubility profiles,melting point temperatures, hygroscopicity, particle shape, density,flowability, compactibility and x-ray diffraction peaks. In certainembodiments, compounds of Formula (I) are obtained in crystalline form.In addition, certain crystalline forms of compounds of Formula (I) orpharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R-OH encompassesreference to any one of, for example, R-OH(s), R-OH(sol), and R-O-(sol).In this example, R-OH(s) refers to the solid compound, as it could befor example in a tablet or some other solid pharmaceutical compositionor preparation; R-OH(sol) refers to the undissociated form of thecompound in a solvent; and R-O-(sol) refers to the dissociated form ofthe compound in a solvent, such as the dissociated form of the compoundin an aqueous environment, whether such dissociated form derives fromR-OH, from a salt thereof, or from any other entity that yields R-O-upon dissociation in the medium being considered.

In another example, an expression such as “modulate activity of PDE1 oran associated signaling pathway” refers to the exposure of PDE1 to theform, or forms, of the compound

R-OH that exists, or exist, in the medium in which such exposure takesplace. In this regard, if such compound is, for example, in an aqueousenvironment, it is understood that the compound R-OH is in the same suchmedium, and therefore PDE1 is being exposed to the compound as it existsin the medium such as R-OH (aq) and/or R-O- (aq), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A hydroxyl functional group has been chosenin these nomenclature examples; this choice is not intended, however, asa limitation but is merely an illustration. It is understood thatanalogous examples can be provided in terms of other functional groups,including, but not limited to, basic nitrogen members, such as those inamines, and any other group that interacts or transforms according toknown manners in the medium that contains the compound. Suchinteractions and transformations include, but are not limited to,dissociation, association, tautomerism, solvolysis, includinghydrolysis, solvation, including hydration, protonation anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

Salts

Embodiments include pharmaceutically acceptable salts of the compoundsrepresented by Formula (I), and methods using such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G.S. Paulekuhn etal., 2007, J. Med. Chem. 50, 6665-6672; Berge et al., 1977, J. Pharm.Sci. 66, 1-19; Stahl and Wermuth (eds), Pharmaceutical Salts:Properties, Selection, and Use: 2nd Revised Edition (2011) Wiley-VCS,Zurich, Switzerland. Examples of pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of patients without undue toxicity, irritation, or allergicresponse. A compound of Formula (I) may possess a sufficiently acidicgroup, a sufficiently basic group, or both types of functional groups,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form pharmaceutically acceptable saltbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2- acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Prodrugs

Some embodiments provide prodrugs of the compounds of Formula (I), andthe use of such pharmaceutically acceptable prodrugs in methods of thepresent disclosure, particularly therapeutic methods.

The term “prodrug” means a precursor of a designated compound that isinitially inactive or partially inactive, and that followingadministration to a subject, yields the compound in vivo via a chemicalor physiological process such as solvolysis or enzymatic cleavage, orunder physiological conditions (e.g., a prodrug on being brought tophysiological pH is converted to an active pharmacological compound ofFormula (I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is preferablynon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Prodrugs are often useful because, insome situations, they can be easier to administer than the parent drug.They can, for instance, be bioavailable by oral administration whereasthe parent is not. The prodrug can also have improved solubility inpharmaceutical compositions over the parent drug.

Prodrugs may be determined using routine techniques known or availablein the art Prodrugs may be produced, for instance, by derivatizing freecarboxyl groups, free hydroxy groups, or free amino groups. See, e.g.,Bundgaard (ed.), 1985, Design of prodrugs, Elsevier; Krogsgaard-Larsenet al., (eds.), 1991, Design and Application of Prodrugs, HarwoodAcademic Publishers; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19,115-130; Robinson et al., 1996, J. Med. Chem. 39, 10-18.

Tautomers

Some embodiments provide tautomers of compounds of Formula (I), asdefined further herein, which may also be used in the methods of thedisclosure.

Metabolites

Some embodiments provide pharmaceutically active metabolites of thecompounds of Formula (I), which may also be used in the methods of thedisclosure. A “pharmaceutically active metabolite” means apharmacologically active product of metabolism in the body of a compoundof Formula (I) or salt thereof. Preferably, the metabolite is in anisolated form outside the body.

Active metabolites of a compound may be determined using routinetechniques known or available in the art. For example, isolatedmetabolites can be enzymatically and synthetically produced (e.g.,Bertolini et al., 1997, J. Med. Chem. 40, 2011-2016; Shan et al., 1997,J. Pharm. Sci. 86, 765-767; Bagshawe, 1995, Drug Dev. Res. 34, 220-230;and Bodor, 1984, Adv. Drug Res. 13, 224-231).

Isotopes

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of the element. Any formulagiven herein is also intended to represent unlabeled forms as well asisotopically-labeled forms of the compounds. Isotopically-labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the embodiments include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶C1,and ¹²⁵I, respectively.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s) (e.g., one ormore of the presently disclosed chemical entities), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a chemical entityof Formula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” can alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I), aspreviously defined herein. The term “carrier” refers to an adjuvant,vehicle, or excipients, with which the compound is administered. Inpreferred embodiments of this invention, the carrier is a solid carrier.Suitable pharmaceutical carriers include those described in Remington:The Science and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

As used herein, “suitable for oral administration” refers to a sterile,pharmaceutical product produced under good manufacturing practices (GMP)that is prepared and presented in a manner such that the composition isnot likely to cause any untoward or deleterious effects when orallyadministered to a subject. Unless specified otherwise, all of thecompositions disclosed herein are suitable for oral administration.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease’s cause, transmission, or expression) or notdirectly affecting the disease. Particularly with respect to progressivedisease-states or conditions, maintaining the status quo, or arrestingthe progression of symptoms, is understood to be an amelioration of suchsymptoms.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal). An“effective amount” also means an amount or dose of a compound orcomposition effective to modulate activity of PDE1 or an associatedsignaling pathway. The “effective amount” will vary, depending on thecompound, the disease, the type of treatment desired, and its severity,and age, weight, etc.

As used herein, the term “PDE1” refers to all translation products codedby transcripts of any or all three genes, PDE1A, PDE1B, and PDE1C. Theamino acid and nucleotide sequences that encode PDE1 of various speciesare known to those skilled in the art and can be found, for example, inGenBank under accession numbers AJ401610.1, AJ401609.1, and Fiddock etal., 2002, Cell. Sign al. 14, 53-60.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to (or“compared to”) the normal long term memory formation of the animal orcontrols. As a result, long term memory acquisition is faster or betterretained. Enhancing performance of a cognitive task refers to theability to potentiate or improve performance of a specified cognitivetask by an animal relative to the normal performance of the cognitivetask by the animal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.”

Reference will now be made to embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying examples. While certain embodiments are describedherein, it is understood that the described embodiments are not intendedto limit the scope of the invention. On the contrary, the presentdisclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

CHEMICAL ENTITIES

Some embodiments provide certain substituted furanopyrimidine chemicalentities which are useful, for example, as inhibitors of PDE1 enzymaticactivity.

In some embodiments, the chemical entities include the compoundsdisclosed herein and pharmaceutically acceptable salts, chelates,solvates, conformers, crystalline forms/polymorphs, tautomers, prodrugs,metabolites, and mixtures thereof. In some embodiments, the chemicalentities include the compounds disclosed herein and pharmaceuticallyacceptable salts thereof.

Some embodiments provide a chemical entity of Formula (I):

wherein, R^(a) has any of the values described herein.

In some embodiments of a chemical entity of Formula (I),

R^(a) is -L¹-L³, -L¹-L²-L³, or -N(L⁴)-L⁵;

-   L¹ is selected from the group consisting of: -N(R^(b))-,    -N(R^(b))-(C(R^(b))₂)m-, -N(R^(b))(CH₂)_(m)O-, -NHNH-, 3-15-membered    heterocycloalkyl, and 5-10-membered heteroaryl, said 3-15-membered    heterocycloalkyl or 5-10-membered heteroaryl optionally substituted    with one to four R^(1A), where each R^(1A) is independently selected    from the group consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,    -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋ ₆haloalkyl,-   -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl;    -   each m is independently 0, 1, 2, or 3;    -   each R^(b) is independently —H, —OH, -C₁₋₆alkyl, -C₁₋₆haloalkyl,        -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl,        -C₃₋₇cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   L² is selected from the group consisting of: —N(R^(c))—,    —N(R^(c))(CH₂)_(m-), —O—, —S—, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₂₋₆alkenyl, -C₂₋₆alkynyl,    -C(O)C₁₋₆alkyl, -CHR^(c)-, —(CH₂)_(m)NH—, —(CH₂)_(m)O—,    —(CH₂)_(m)S—, -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl,    phenyl, benzyl, and 5-10-membered heteroaryl, said -C₁₋₆alkyl,    -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, and    5-10-membered heteroaryl optionally substituted with one to four    R^(1B), where each R^(1B) is independently selected from the group    consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,    —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,    -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋ ₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, -C₃₋₇cycloalkyl,    3-15-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl;    -   each R^(c) is independently —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl,        -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl,        -C₃₋₇cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   L³ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋ ₄alkyl)₂, -N(R^(1DD))₂, —N═S(═O)(CH₃)₂, —NO₂,    —SO₂CH₃, halo, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋ ₆alkoxy,-   -C₁₋₆haloalkoxy, -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl,    —C(O)NH₂, -C₁₋₆alkyl-O-C₁₋ ₄alkyl, -C₃₋₁₀cycloalkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl,    phenyl, benzyl, and 5-10-membered heteroaryl optionally substituted    with one to four R^(1C), where each R^(1C) is independently selected    from the group consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,-   -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, -C₃₋₇cycloalkyl,    3-15-membered heterocycloalkyl, phenyl and 5-10-membered heteroaryl;-   each R^(1DD) is independently selected from the group consisting of:    —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,    -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl,    -C₃₋₇cycloalkyl, 3-15-membered heterocycloalkyl, phenyl and    5-10-membered heteroaryl;-   L⁴ and L⁵ taken together with the nitrogen to which they are    attached to form a 3-15-membered heterocycloalkyl or 5-10-membered    heteroaryl ring, optionally substituted with one to four R^(1D),    where each R^(1D) is independently selected from the group    consisting of: L⁶, =O,-   -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, and -COOC₁₋₆alkyl; and-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋ ₄alkyl)₂, —N═S(═O)(CH₃)₂, —NO₂, —SO₂CH₃, halo,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl, —C(O)NH₂,    -C₃₋₁₀cycloalkyl, -C₁₋₆alkyl-O-C₁₋₄alkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl,    phenyl, benzyl, and 5-10-membered heteroaryl optionally substituted    with one to four R^(1E), where each R^(1E) is independently selected    from the group consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,-   -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, -C₃₋₇cycloalkyl,    3-15-membered heterocycloalkyl, phenyl and 5-10-membered heteroaryl.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ia), and more particularly, is a compound of Formula(Ia), or a pharmaceutically acceptable salt of a compound of Formula(Ia):

wherein L¹ and L³ have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Ia),

-   L¹ is selected from the group consisting of: —N(R^(b))—,    —N(R^(b))—(CR^(b) ₂)_(m)—, —N(Rb)(CH₂)_(m)O—, -NHNH-, 3-15-membered    heterocycloalkyl, and 5-10-membered heteroaryl, said 3-15-membered    heterocycloalkyl or 5-10-membered heteroaryl optionally substituted    with one to four R^(1A), where each R^(1A) is independently selected    from the group consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,    -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl;    -   each m is independently 0, 1, 2, or 3;    -   each R^(b) is independently —H, —OH, -C₁₋₆alkyl, -C₁₋₆haloalkyl,        -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl,        -C₃₋₇cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl.-   L³ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, -N(R^(1DD))₂, —N═S(═O)(CH₃)₂, —NO₂,    —SO₂CH₃, halo, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy,    -C₁₋₆haloalkoxy, -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, —C(O)NH₂, -C₃₋₁₀cycloalkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl, -C₃₋₇cycloalkoxy, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl    optionally substituted with one to four R^(1C), where each R^(1C) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂,    -C₃₋₇cycloalkyl, 3-15-membered heterocycloalkyl, phenyl and    5-10-membered heteroaryl; and    -   each R^(1DD) is independently selected from the group consisting        of: —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,        -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl,        -C₃₋₇cycloalkyl, 3-15-membered heterocycloalkyl, phenyl and        5-10-membered heteroaryl.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ib), and more particularly, is a compound of Formula(Ib), or a pharmaceutically acceptable salt of a compound of Formula(Ib):

wherein L¹, L², and L³ have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Ib),

-   L¹ is selected from the group consisting of: —N(R^(b))—,    —N(R^(b))—(CR^(b) ₂)_(m)—, —N(R^(b))(CH₂)_(m)O—, -NHNH-,    3-15-membered heterocycloalkyl, and 5-10-membered heteroaryl, said    3-15-membered heterocycloalkyl or 5-10-membered heteroaryl    optionally substituted with one to four R^(1A), where each R^(1A) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and    -C₃₋₇cycloalkyl;    -   each m is independently 0, 1, 2, or 3;    -   each R^(b) is independently —H, —OH, -C₁₋₆alkyl, -C₁₋₆haloalkyl,        -C₁₋₆alkyl-OH,    -   -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -C₃₋₇cycloalkyl,        -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   L² is selected from the group consisting of: —N(R^(c))—,    —N(R^(c))(CH₂)_(m)—, —O—, —S—, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₂₋₆alkenyl, -C₂₋₆alkynyl,    -C(O)C₁₋₆alkyl, -CHR^(c)-, —(CH₂)_(m)NH—, —(CH₂)_(m)O—,    —(CH₂)_(m)S—, -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl,    phenyl, benzyl, and 5-10-membered heteroaryl, said -C₁₋₆alkyl,    -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, and    5-10-membered heteroaryl optionally substituted with one to four    R^(1B), where each R^(1B) is independently selected from the group    consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, N(C₁₋₄alkyl)₂,    —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,-   -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, -C₃₋₇cycloalkyl,    3-15-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl;    -   each R^(c) is independently —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl,        -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl,        -C₃₋₇cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   L³ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, -N(R^(1DD))₂, —N═S(═O)(CH₃)₂, —NO₂,    —SO₂CH₃, halo, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy,    -C₁₋₆haloalkoxy, -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, —C(O)NH₂, -C₃₋₁₀cycloalkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl, -C₃₋₇cycloalkoxy, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl    optionally substituted with one to four R^(1C), where each R^(1C) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂,    -C₃₋₇cycloalkyl, 3-15-membered heterocycloalkyl, phenyl and    5-10-membered heteroaryl; and    -   each R^(1DD) is independently selected from the group consisting        of: —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,        -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl,        -C₃₋₇cycloalkyl, 3-15-membered heterocycloalkyl, phenyl and        5-10-membered heteroaryl.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

-   L¹ is selected from a group consisting of: —N(R^(b))—,    —N(R^(b))—(CR^(b) ₂)_(m)—, —N(R^(b))(CH₂)_(m)O—, and -NHNH-;-   each m is independently 0, 1, 2, or 3; and-   each R^(b) is independently —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl,    -C₃₋₇cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

-   L¹ is —N(R^(b))— or —N(R^(b))—(CR^(b) ₂)_(m)—;-   each m is independently 0, 1, 2, or 3; and-   each R^(b) is independently —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, or    -C₃₋₇cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is —NH— or —NHCH₂—.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein: L¹ is a 3-15-membered heterocycloalkyl or5-10-membered heteroaryl, said 3-15-membered heterocycloalkyl or5-10-membered heteroaryl optionally substituted with one to four R^(1A).

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of: azetidine, pyrrolidine,2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine,piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine,piperazine, morpholine, 3-azabicyclo[3.1.0]hexane,octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole,6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,5,6,7,8-tetrahydro-1,6-naphthyridine,5,6,7,8-tetrahydro-1,7-naphthyridine,1,2,3,4-tetrahydro-2,6-naphthyridine,1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline,5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine,5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one,4,5,6,7-tetrahydrothieno[3,2-c]pyridine,octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole,hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole,decahydroisoquinoline, decahydroquinoline, azepane, diazepane,8-oxa-3-azabicyclo[3.2.1]octane,6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine,3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine,spiro[indoline-3,3′-piperidin]-2-one,spiro[indoline-3,3′-pyrrolidin]-2-one,2,3-dihydrospiro[indene-1,2′-morpholine],3H-spiro[isobenzofuran-1,3′-piperidine],3H-spiro[isobenzofuran-1,3′-pyrrolidine], spiro [benzo [d][1,3]oxazine-4,4′-piperidin]-2(1H)-one, spiro [indene-1,4′-piperidine],3H-spiro[benzo[c]thiophene-1,4′-piperidine], and2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine, said 3-15-memberedheterocycloalkyl optionally substituted with one to four R^(1A).

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of: azetidine, pyrrolidine,piperidine, azepane, 1,2,3,6-tetrahydropyridine,1,2,3,4-tetrahydropyridine, and 2,3-dihydro-1H-pyrrole.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of: imidazolidine, piperazine,diazepane and morpholine.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of:6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,5,6,7,8-tetrahydro-1,6-naphthyridine,5,6,7,8-tetrahydro-1,7-naphthyridine,1,2,3,4-tetrahydro-2,6-naphthyridine,1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, and isoindoline.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of:5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,4,5,6,7-tetrahydropyrazolo[1,5-α]pyrazine,octahydropyrrolo[1,2-a]pyrazine, and octahydropyrrolo[1,2-c]pyrimidine.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is selected from the group consisting of: 3-azabicyclo[3.1.0]hexane,octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole,4,5,6,7-tetrahydrothieno[3,2-c]pyridine,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole,hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole,decahydroisoquinoline, decahydroquinoline,8-oxa-3-azabicyclo[3.2.1]octane,6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine,3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine,spiro[indoline-3,3′-piperidin]-2-one,spiro[indoline-3,3′-pyrrolidin]-2-one,2,3-dihydrospiro[indene-1,2′-morpholine],3H-spiro[isobenzofuran-1,3′-piperidine],3H-spiro[isobenzofuran-1,3′-pyrrolidine], spiro [benzo[d][1,3]oxazine-4,4′-piperidin] -2(1H)-one, spiro[indene-1,4′-piperidine], 3H-spiro[benzo[c]thiophene-1,4′-piperidine],and 2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a 5-10-membered heteroaryl selected from the group consisting of:pyrazole, imidazole, pyrrole, oxazole, thiazole, indole, and indazole,said 5-10-membered heteroaryl optionally substituted with one to fourR^(1A).

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is pyrazole, optionally substituted with one to four R^(1A).

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein: R^(a) is -L¹-L³ or -L¹-L²-L³, and R^(1A) isindependently selected from the group consisting of: halo, —OH, ═O,—NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋ ₆alkyl,-C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,-C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and-C₃₋₇cycloalkyl.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Iba), and more particularly, is a compound of Formula(Iba), or a pharmaceutically acceptable salt of a compound of Formula(Iba):

wherein R^(b), L², m, and L³ have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Iba),

-   L² is -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, or    5-10-membered heteroaryl, said -C₃₋₁₀cycloalkyl, 3-15-membered    heterocycloalkyl, phenyl, and 5-10-membered heteroaryl optionally    substituted with one to four R^(1B), where each R^(1B) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, —CN, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, and    -C₁₋₆alkyl-O-C₁₋₄alkyl;-   R^(b) is —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,    -C₃₋₆cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   L³ is —H, —OH, —CN, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, halo,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, benzyl, or    5-10-membered heteroaryl, said -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl,    3-15-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl optionally substituted with one to four R^(1C), where    each R^(1C) is independently selected from the group consisting of:    halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, —CN,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy,    -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl; and-   m is 0, 1 or 2.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ibb), and more particularly, is a compound of Formula(Ibb), or a pharmaceutically acceptable salt of a compound of Formula(Ibb):

wherein R^(b), R^(d), m, L², and L³ have any of the values describedherein.

In certain embodiments of a chemical entity of Formula (Ibb),

-   L² is -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, or    5-10-membered heteroaryl, said -C₃₋₁₀cycloalkyl, 3-15-membered    heterocycloalkyl, phenyl, and 5-10-membered heteroaryl optionally    substituted with one to four R^(1B), where each R^(1B) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, —CN, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, and    -C₁₋₆alkyl-O-C₁₋₄alkyl;-   L³ is —H, —OH, —CN, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, halo,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, benzyl, or    5-10-membered heteroaryl, said -C₁₋₆alkyl, -C₃₋₁₀cycloalkyl,    3-15-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl optionally substituted with one to four R^(1C), where    each R^(1C) is independently selected from the group consisting of:    halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,—NO₂, —CN,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy,    -C₁₋₆haloalkoxy, and -C₁₋₆alkyl-O-C₁₋₄alkyl;-   R^(b) is —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,    -C₃₋₆cycloalkyl, -C₂₋₆alkenyl, or -C₂₋₆alkynyl;-   each R^(d) is independently selected from the group consisting of:    —H, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₃₋₆cycloalkyl; and-   m is 0, 1 or 2.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Ic), and more particularly, is a compound of Formula(Ic), or a pharmaceutically acceptable salt of a compound of Formula(Ic):

wherein L⁴ and L⁵ have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Ic),

-   L⁴ and L⁵ are taken together with the nitrogen to which they are    attached to form a 3-15-membered heterocycloalkyl or 5-10-membered    heteroaryl ring, optionally substituted with one to four R^(1D),    where each R^(1D) is independently selected from the group    consisting of: L⁶, =O, -C₁₋ ₆alkyl-OH,-   -C₁₋₆alkyl-O-C₁₋₄alkyl, and -COOC₁₋₆alkyl; and-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —N═S(═O)(CH₃)₂, —NO₂, —SO₂CH₃, halo,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl, —C(O)NH₂,    -C₃₋₁₀cycloalkyl, -C₁₋₆alkyl-O-C₁₋₄alkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋ ₆alkyl, -C₃₋₁₀cycloalkyl, -C₃₋₇cycloalkoxy, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl    optionally substituted with one or more R^(1E), where each R^(1E) is    independently selected from the group consisting of: halo, —OH, ═O,    —NH₂, -NHC₁₋₄alkyl, -N(C₁₋ ₄alkyl)₂, —NO₂,-   —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,    -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋ ₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, -C₃₋₇cycloalkyl,    3-15-membered heterocycloalkyl, phenyl and 5-10-membered heteroaryl.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icaa) or (Icab), and more particularly, is a compoundof Formula (Icaa) or (Icab), or a pharmaceutically acceptable salt of acompound of Formula (Icaa) or (Icab):

, wherein L⁶, B¹, B² and p have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Icaa) or (Icab),

-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, halo, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₂₋₆alkenyl,    -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl, —C(O)NH₂, -C₃₋₁₀cycloalkyl,    -C₁₋₆alkyl-O-C₁₋₄alkyl, -3-15-membered heterocycloalkyl, phenyl,    benzyl, and 5-10-membered heteroaryl, said -C₁₋ ₆alkyl,-   -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, benzyl,    and 5-10-membered heteroaryl optionally substituted with one to four    R^(1E), where each R^(1E) is independently selected from the group    consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,    -N(C₁₋₄alkyl)₂,—NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl;-   B¹ is CH or C(R^(1D));-   B² is CH₂ or CH(R^(1D));-   R^(1D) is L⁶, ═O, -C₁₋₆alkyl-OH, or -C₁₋₆alkyl-O-C₁₋₄alkyl; and-   p is 0, 1, 2 or 3.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icb), and more particularly, is a compound of Formula(Icb), or a pharmaceutically acceptable salt of a compound of Formula(Icb):

wherein L⁶, B², Q, and q have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Icb),

-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, halo, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₂₋₆alkenyl,    -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl, —C(O)NH₂, -C₃₋₁₀cycloalkyl,    -C₁₋₆alkyl-O-C₁₋₄alkyl, 3-15-membered heterocycloalkyl, phenyl,    benzyl, and 5-10-membered heteroaryl, said -C₁₋₆alkyl, -C₃₋    ₁₀cycloalkyl, 3-15-membered heterocycloalkyl, phenyl, benzyl, and    5-10-membered heteroaryl optionally substituted with one to four    R^(1E), where each R^(1E) is independently selected from the group    consisting of: halo, —OH, =O, —NH₂, -NHC₁₋₄alkyl,    -N(C₁₋₄alkyl)₂,—NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl;-   B² is CH₂ or CH(R^(1D));-   R^(1D) is L⁶, ═O, -C₁₋₆alkyl-OH, or -C₁₋₆alkyl-O-C₁₋₄alkyl;-   Q is NH, N(R^(1D)), or O; and-   each q is 1, 2, or 3.

In certain embodiments, a chemical entity of Formula (I) is a chemicalentity of Formula (Icc), and more particularly, is a compound of Formula(Icc), or a pharmaceutically acceptable salt of a compound of Formula(Icc):

wherein L⁶, B¹, D¹, E, G, and r have any of the values described herein.

In certain embodiments of a chemical entity of Formula (Icc),

-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —N═S(═O)(CH₃)₂, —NO₂, —SO₂CH₃, halo,    -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,    -C₂₋₆alkenyl, -C₂₋₆alkynyl, -C(O)C₁₋₆alkyl, —C(O)NH₂,    -C₃₋₁₀cycloalkyl, -C₁₋₆alkyl-O-C₁₋₄alkyl, 3-15-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋ ₆alkyl, -C₃₋₁₀cycloalkyl, 3-15-membered heterocycloalkyl,    phenyl, benzyl, and 5-10-membered heteroaryl optionally substituted    with one to four R^(1E), where each R^(1E) is independently selected    from the group consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,    -N(C₁₋₄alkyl)₂,—NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl,    -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋₄alkyl,    -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl;-   each B¹, D¹, E, and G is either CH, C(R^(1D)), or N, provided that    no more than two of B¹, D¹, E, and G are simultaneously N;-   each R^(1D) is independently selected from the group consisting of:    L⁶, =O, -C₁₋₆alkyl-OH, and -C₁₋₆alkyl-O-C₁₋₄alkyl; and-   r is 1 or 2.

In some embodiments of a chemical entity of Formula (Icc) disclosedherein:

-   L⁶ is selected from the group consisting of: —H, halo, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkoxy, and -C₁₋₆haloalkoxy;-   B¹ and E are N;-   D¹ and G are independently CH or C(R^(1D));-   and r is 2.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

-   L⁶ is selected from the group consisting of: —H, halo, -C₁₋₆alkyl,    -C₁₋₆haloalkyl, -C₁₋₆alkoxy, and -C₁₋₆haloalkoxy;-   D¹ and G are N;-   B¹ and E are independently CH or C(R^(1D));-   and r is 2.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is —N(R^(c))—, —NR^(c)(CH₂)_(m)—, —O—, —S—, -C₁₋₄alkyl,-C₁₋₄haloalkyl, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy, -C₂₋₅alkenyl,-C₂₋₅alkynyl, -C(O)C₁₋₄alkyl, -CHR^(c)-, —(CH₂)_(m)NH—, —(CH₂)_(m)O—, or—(CH₂)_(m)S—, said -C₁₋₄alkyl optionally substituted with one to threeR^(1B), where each R^(1B) is independently selected from the groupconsisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,-N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl,-C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy, -C₁₋₄alkyl-O-C₁₋₄alkyl,-C(O)C₁₋₄alkyl, -COOC₁₋₄alkyl, —C(O)NH₂, and -C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is selected from the group consisting of: -C₃₋₁₀cycloalkyl,3-10-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl,said -C₃₋₁₀cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, and5-10-membered heteroaryl optionally substituted with one to threeR^(1B).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[1.1.1]pentan-1-yl, adamantanyl, or 2,3-dihydro-1H-inden-5-yl,each optionally substituted with one to three R^(1B).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is selected from the group consisting of: azetidine, pyrrolidine,piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline,piperazine, diazepane, morpholine, oxetane, tetrahydrofuran,tetrahydropyran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine,tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one,decahydroisoquinoline, decahydroquinoline,6,7-dihydro-5H-cyclopenta[b]pyridine,6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxine,pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane,8-oxa-3-azabicyclo[3.2.1]octane, pyrimidin-4(3H)-one,octahydrocyclopentapyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine,6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, and isoindoline, each optionallysubstituted with one to four R^(1B), where each R^(1B) is independentlyselected from the group consisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂,-NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₄alkyl,-C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy,-C₁₋₄alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₄alkyl, -COOC₁₋₄alkyl, —C(O)NH₂, and-C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is selected from the group consisting of: azetidine, pyrrolidine,piperidine, azepane, imidazoline, piperazine, diazepane, morpholine,oxetane, tetrahydrofuran, tetrahydropyran, benzo [d] [1,3]dioxole,2,3-dihydrobenzo[b] [1,4] dioxine, tetrahydroquinoline,tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline,decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine,6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3 -dihydrobenzo [b] [1,4]dioxine, pyrimidinone, 3-oxabicyclo[3.1.0]hexane,3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, andpyrimidin-4(3H)-one, each optionally substituted with one to threeR^(1B), where each R^(1B) is independently selected from the groupconsisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —CN,-C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy,-C₁₋₄alkyl-O-C₁₋₄alkyl, -C(O)C₁₋ ₄alkyl, -COOC₁₋₄alkyl, —C(O)NH₂, and-C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is phenyl, optionally substituted with one to three R^(1B).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is a 5-10-membered heteroaryl selected from the group consisting of:pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, furan, thiophene,pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole,triazole, oxadiazole, thiadiazole, tetrazole, indole, indazole,benzimidazole, benzoxazole, benzothiazole,[1,2,4]triazolo[4,3-a]pyridine, and imidazo[1,2-a]pyrazine, eachoptionally substituted with one to three R^(1B), where each R^(1B) isindependently selected from the group consisting of: halo, —OH, ═O,—NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₄alkyl,-C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy,-C₁₋₄alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₄alkyl, -COOC₁₋₄alkyl, —C(O)NH₂, and-C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L² is pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole,imidazole, thiazole, oxazole, and isoxazole, each optionally substitutedwith one to three R^(1B), where each R^(1B) is independently selectedfrom the group consisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂,-NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₄alkyl,-C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy,-C₁₋₄alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₄alkyl, -COOC₁₋₄alkyl, —C(O)NH₂, and-C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: —H, —OH, —CN, —NH₂,-NHC₁₋₄alkyl,-N(C₁₋₄alkyl)₂, —N═S(═O)(CH₃)₂, —NO₂, —SO₂CH₃, —F, —Cl,—Br, —I, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy,-C₂₋₅salkenyl, -C₂₋₅alkynyl, -C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, and-C(O)NH₂, said -C₁₋₄alkyl, optionally substituted with one to threeR^(1C).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: —H, —OH, —CN, —NH₂,-NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —F, —Cl, —Br, —I, -C₁₋₄alkyl,-C₁₋₄haloalkyl, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy, said -C₁₋₄alkyl,optionally substituted with one to three R^(1C).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: -C₃₋₁₀cycloalkyl,3-10-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl,said -C₃₋₁₀cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, and5-10-membered heteroaryl optionally substituted with one to threeR^(1C).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl,bicyclo[1.1.1]pentan-1-yl, adamantanyl, or 2,3-dihydro-1H-inden-5-yl,each optionally substituted with one to three R^(1C).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: azetidine, pyrrolidine,piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline,piperazine, diazepane, morpholine, oxetane, tetrahydrofuran,tetrahydropyran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine,tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one,decahydroisoquinoline, decahydroquinoline,6,7-dihydro-5H-cyclopenta[b]pyridine,6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxine,pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane,8-oxa-3-azabicyclo[3.2.1] octane, pyrimidin-4(3H)-one,octahydrocyclopentapyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine,6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, and isoindoline, each optionallysubstituted with one to three R^(1C), where each R^(1C) is independentlyselected from the group consisting of: halo, —OH, =O, —NH₂,-NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —SO₂CH₃, —CN, -C₁₋₆alkyl,-C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy,-C₁₋₆alkyl-O-C₁₋₄alkyl, -C(O)C₁₋₆alkyl, -COOC₁₋₆alkyl, —C(O)NH₂, and-C₃₋₇cycloalky1.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: azetidine, pyrrolidine,piperidine, azepane, imidazoline, piperazine, diazepane, morpholine,oxetane, tetrahydrofuran, tetrahydropyran, benzo [d][1,3]dioxole,2,3-dihydrobenzo[b][1,4] dioxine, tetrahydroquinoline,tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline,decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine,6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3 -dihydrobenzo [b][1,4]dioxine, pyrimidinone, 3-oxabicyclo[3.1.0]hexane,3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, andpyrimidin-4(3H)-one, each optionally substituted with one to threeR^(1C), where each R^(1C) is independently selected from the groupconsisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,-N(C₁₋₄alkyl)₂, —CN, -C₁₋ ₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH,-C₁₋₄alkoxy, -C₁₋₄haloalkoxy, -C₁₋₄alkyl-O-C₁₋₄alkyl, and-C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is phenyl, optionally substituted with one to three R^(1C).

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: pyridine, pyridazine,pyrazine, pyrimidine, pyrrole, furan, thiophene, pyrazole, imidazole,thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole,thiadiazole, tetrazole, indole, indazole, benzimidazole, benzoxazole,benzothiazole, [1,2,4]triazolo[4,3-a]pyridine, andimidazo[1,2-a]pyrazine, each optionally substituted with one to fourR^(1C), where each R^(1C) is independently selected from the groupconsisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂, -NHC₁₋₄alkyl,-N(C₁₋₄alkyl)₂, —CN, -C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH,-C₁₋₆alkoxy, -C₁₋₆haloalkoxy, -C₁₋₆alkyl-O-C₁₋aalkyl, -C(O)C₁₋₆alkyl,-COOC₁₋₆alkyl, —C(O)NH₂, and -C₃₋₇cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: pyridine, pyridazine,pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole,and isoxazole, each optionally substituted with one to three R^(1C),where each R^(1C) is independently selected from the group consistingof: —F, —Cl, —Br, —I, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —CN,-C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxyand -C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is selected from the group consisting of: pyrrole, pyrazole,imidazole, thiazole, oxazole, and isoxazole, each optionally substitutedwith one to three R^(1C), where each R^(1C) is independently selectedfrom the group consisting of: —F, —Cl, —Br, —I, —OH, ═O, —NH₂,-NHC₁₋₄alkyl, -N(C₁₋ ₄alkyl)₂, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl,-C₁₋₄alkyl-OH, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy, and -C₃₋ ₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein: L⁴ and L⁵ are taken together with the nitrogen towhich they are attached to form a azetidine, pyrrolidine,2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine,piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine,piperazine, morpholine, 3-azabicyclo[3.1.0]hexane,octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole,6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-5H-pyrrolo[3,2-J]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,5,6,7,8-tetrahydro-1,6-naphthyridine,5,6,7,8-tetrahydro-1,7-naphthyridine,1,2,3,4-tetrahydro-2,6-naphthyridine,1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline,5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine,5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one,4,5,6,7-tetrahydrothieno[3,2-c]pyridine,octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole,hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole,decahydroisoquinoline, decahydroquinoline, azepane, diazepane,8-oxa-3-azabicyclo[3.2.1]octane,6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine,3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine,spiro[indoline-3,3′-piperidin]-2-one,spiro[indoline-3,3′-pyrrolidin]-2-one,2,3-dihydrospiro[indene-1,2′-morpholine],3H-spiro[isobenzofuran-1,3′-piperidine],3H-spiro[isobenzofuran-1,3′-pyrrolidine],spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one,spiro[indene-1,4′-piperidine],3H-spiro[benzo[c]thiophene-1,4′-piperidine], or2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine, each optionallysubstituted with one to three R^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein: L⁴ and L⁵ are taken together with the nitrogen towhich they are attached to form a azetidine, pyrrolidine, piperidine,azepane, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, or2,3-dihydro-1H-pyrrole, each optionally substituted with one to threeR^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein: L⁴ and L⁵ are taken together with the nitrogen towhich they are attached to form a imidazolidine, piperazine, diazepane,or morpholine, each optionally substituted with one to three R^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein: L⁴ and L⁵ are taken together with the nitrogen towhich they are attached to form a6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine,6,7-dihydro-577-pyrrolo[3,2-d]pyrimidine,5,6,7,8-tetrahydropyrido[4,3-c]pyridazine,5,6,7,8-tetrahydropyrido[3,4-c]pyridazine,5,6,7,8-tetrahydropyrido[3,2-c]pyridazine,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine,5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,5,6,7,8-tetrahydro-1,6-naphthyridine,5,6,7,8-tetrahydro-1,7-naphthyridine,1,2,3,4-tetrahydro-2,6-naphthyridine,1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, or isoindoline, each optionallysubstituted with one to three R^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ are taken together with the nitrogen to which they areattached to form a 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, octahydropyrrolo [1,2-a]pyrazine, oroctahydropyrrolo[1,2-c]pyrimidine, each optionally substituted with oneto three R^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ are taken together with the nitrogen to which they areattached to form a: 3-azabicyclo[3.1.0]hexane,octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole,4,5,6,7-tetrahydrothieno[3,2-c]pyridine,hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole,hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole,decahydroisoquinoline, decahydroquinoline,8-oxa-3-azabicyclo[3.2.1]octane,6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine,3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine,spiro[indoline-3,3′-piperidin]-2-one,spiro[indoline-3,3′-pyrrolidin]-2-one,2,3-dihydrospiro[indene-1,2′-morpholine],3H-spiro[isobenzofuran-1,3′-piperidine],3H-spiro[isobenzofuran-1,3′-pyrrolidine],spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one,spiro[indene-1,4′-piperidine],3H-spiro[benzo[c]thiophene-1,4′-piperidine], or2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine, each optionallysubstituted with one to three R^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ are taken together with the nitrogen to which they areattached to form a pyrazole, imidazole, pyrrole, oxazole, thiazole,indole, or indazole, each optionally substituted with one to threeR^(1D),

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ are taken together with the nitrogen to which they areattached to form a pyrazole, optionally substituted with one to threeR^(1D),

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

each R^(b) is independently —H, -C₁₋₃alkyl, -C₁₋₃haloalkyl,-C₁₋₃alkyl-OH, -C₁₋₃alkyl-O-C₁₋₃alkyl, or -C₃₋₅cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb), or (Icc) disclosed herein:

-   L⁶ is selected from the group consisting of: —H, —OH, —CN, —NH₂,    -NHC₁₋₄alkyl, -N(C₁₋ ₄alkyl)₂, —F, —Cl, —Br, —I, -C₁₋₄alkyl,    -C₁₋₄haloalkyl, -C₁₋₄alkoxy, -C₁₋₄haloalkoxy, -C(O)C₁₋ ₄alkyl,-   —C(O)NH₂, -C₃₋₁₀cycloalkyl, -C₁₋₄alkyl-O-C₁₋₄alkyl, 3-10-membered    heterocycloalkyl, phenyl, benzyl, and 5-10-membered heteroaryl, said    -C₁₋₄alkyl, -C₃₋₁₀cycloalkyl, -C₃₋ ₇cycloalkoxy,-   3-10-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl optionally substituted with one or more R^(1E), where    each R^(1E) is independently selected from the group consisting of:    halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂, —NO₂, —CN,    -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy,    -C₁₋₄haloalkoxy, -C₁₋₄alkyl-O-C₁₋₄alkyl, and -C₃₋₆cycloalkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

R^(c) is —H, -C₁₋₄alkyl, or -C₁₋₄haloalkyl.

In some embodiments of a chemical entity of Formula (Ibb) disclosedherein:

each R^(d) is independently —H or -C₁₋₄alkyl.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

R^(1B) is independently selected from the group consisting of: —F, —Cl,—OH, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and-C₁₋₄haloalkoxy.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

each R^(1C) is independently selected from the group consisting of: —F,—Cl, —OH, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and-C₁₋₄haloalkoxy.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein: each R^(1D) is independently selected from the groupconsisting of: L⁶ or =O.

In some embodiments of a chemical entity of Formula (I), (Ic), (Ica),(Icb), or (Icc) disclosed herein:

each R^(1E) is independently selected from the group consisting of: —F,—Cl, —OH, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and-C₁₋₄haloalkoxy.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: each R^(b) is independently —H, -C₁₋₆alkyl, or-C₁₋₆haloalkyl.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: m is 0.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: m is 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: m is 2.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein:

-   L² is -C₃₋₇cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, or    5-10-membered heteroaryl, said -C₃₋₇cycloalkyl, 3-10-membered    heterocycloalkyl, phenyl, and 5-10-membered heteroaryl optionally    substituted with one to three R^(1B), where each R^(1B) is    independently selected from the group consisting of: —F, —Cl, —Br,    —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and    -C₁₋₄haloalkoxy;-   L³ is —H, halo, -C₁₋₆alkyl, or -C₁₋₄alkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 0 or 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein:

-   L² is -C₃₋₇cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, or    5-10-membered heteroaryl, said -C₃₋₇cycloalkyl, 3-10-membered    heterocycloalkyl, phenyl, and 5-10-membered heteroaryl optionally    substituted with one to three R^(1B), where each R^(1B) is    independently selected from the group consisting of: —F, —Cl, —Br,    —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and    -C₁₋₄haloalkoxy;-   L³ is -C₃₋₇cycloalkyl, 3-10-membered heterocycloalkyl, phenyl,    benzyl, or 5-10-membered heteroaryl, said -C₃₋₇cycloalkyl,    3-10-membered heterocycloalkyl, phenyl, benzyl, and 5-10-membered    heteroaryl optionally substituted with one to three R^(1C), where    each R^(1C) is independently selected from the group consisting of:    —F, —Cl, —Br, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH,    -C₁₋₄alkoxy, and -C₁₋₄haloalkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 0 or 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: L² is -C₃₋₇cycloalkyl said -C₃₋₇cycloalkyl optionallysubstituted with one to three R^(1B), where each R^(1B) is independentlyselected from the group consisting of: —F, —Cl, —Br, —CN, -C₁₋₄alkyl,and -C₁₋₄haloalkyl;

-   L³ is —H, halo, or -C₁₋₄alkyl;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 0 or 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: L² is phenyl or 5-10-membered heteroaryl, said phenylor 5-10-membered heteroaryl optionally substituted with one to threeR^(1B), where each R^(1B) is independently selected from the groupconsisting of: —F, —Cl, —Br, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl,-C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and -C₁₋₄haloalkoxy;

-   L³ is -C₃₋₇cycloalkyl, 3-10-membered heterocycloalkyl, phenyl, or    5-10-membered heteroaryl, said -C₃₋₇cycloalkyl, 3-10-membered    heterocycloalkyl, phenyl, and 5-10-membered heteroaryl optionally    substituted with one to three R^(1C), where each R^(1C) is    independently selected from the group consisting of: —F, —Cl, —Br,    —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and    -C₁₋₄haloalkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 0 or 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein: L² is phenyl or 5-10-membered heteroaryl, said phenylor 5-10-membered heteroaryl optionally substituted with one to threeR^(1B), where each R^(1B) is independently selected from the groupconsisting of: —F, —Cl, —Br, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl,-C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and -C₁₋₄haloalkoxy;

-   L³ is —H, halo, -C₁₋₆alkyl, or -C₁₋₄alkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 1 or 2.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein:

-   L² is phenyl or 5-6-membered heteroaryl, said phenyl and    5-6-membered heteroaryl optionally substituted with one to three    R^(1B), where each R^(1B) is independently selected from the group    consisting of: —F, —Cl, —Br, -C₁₋₃alkyl, -C₁₋₃haloalkyl,    -C₁₋₃alkoxy, and -C₁₋₃haloalkoxy;-   L³ is —H, -halo, -C₁₋₆alkyl, or -C₁₋₄alkoxy;-   R^(b) is —H or —CH₃; and-   m is 1 or 2.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein:

-   L² is pyridine, pyridazine, pyrazine, or pyrimidine, each optionally    substituted with one to three R^(1B), where each R^(1B) is    independently selected from the group consisting of: —F, —Cl, —Br,    —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy, and    -C₁₋₄haloalkoxy;-   L³ is —H, halo, -C₁₋₆alkyl, or -C₁₋₄alkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 1.

In some embodiments of a chemical entity of Formula (Iba) or (Ibb)disclosed herein:

-   L² is pyrrole, pyrazole, imidazole, thiazole, oxazole or isoxazole,    each optionally substituted with one to three R^(1B), where each    R^(1B) is independently selected from the group consisting of: —F,    —Cl,-   —Br, —CN, -C₁₋₄alkyl, -C₁₋₄haloalkyl, -C₁₋₄alkyl-OH, -C₁₋₄alkoxy,    and -C₁₋₄haloalkoxy;-   L³ is —H, halo, -C₁₋₆alkyl, or -C₁₋₄alkoxy;-   R^(b) is —H, -C₁₋₃alkyl, or -C₁₋₃haloalkyl; and-   m is 1.

In some embodiments of a chemical entity of Formula (Icaa), (Icab),(Icb), or (Icc) disclosed herein:

L⁶ is selected from the group consisting of: —H, —OH, —CN, —NO₂, halo,-C₁₋₆alkyl, -C₁₋₆haloalkyl, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, and-C₃₋₇cycloalkyl.

In some embodiments of a chemical entity of Formula (Icaa), (Icab),(Icb), or (Icc) disclosed herein:

-   L⁶ is phenyl or 5-6-membered heteroaryl, said phenyl and    5-6-membered heteroaryl optionally substituted with one or more    R^(1E), where each R^(1E) is independently selected from the group    consisting of: halo, —OH, ═O, —NH₂, -NHC₁₋₄alkyl, -N(C₁₋₄alkyl)₂,    —NO₂, —CN, -C₁₋ ₆alkyl,-   -C₁₋₆haloalkyl, -C₁₋₆alkyl-OH, -C₁₋₆alkoxy, -C₁₋₆haloalkoxy, and    -C₁₋₆alkyl-O-C₁₋₄alkyl.

In some embodiments of a chemical entity of Formula (Icc) disclosedherein:

r is 2, B¹ is N, E is N, and D¹ and G are independently CH or C(R^(1D))

In some embodiments of a chemical entity of Formula (Icc) disclosedherein:

r is 2, D¹ is N, G is N, and B¹ and E are independently CH or C(R^(1D)).

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is monocyclic or bicyclic 5-10-membered C₄₋₉heteroaryl, comprisingone to three heteroatoms, each independently selected from nitrogen,oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is monocyclic or bicyclic 5-9-membered C₄₋₈heteroaryl, comprising oneto three heteroatoms, each independently selected from nitrogen, oxygen,and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 5-6-membered C₃₋₅heteroaryl, comprising one to threeheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 6-membered C₄₋₅heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 5-membered C₃₋₄heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a bicyclic or tricyclic 9-15-membered C₈₋₁₄heterocycloalkyl,comprising one to three heteroatoms, each independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic or bicyclic 3-10-membered C₂₋₉heterocycloalkyl,comprising one to four heteroatoms, each independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a bicyclic 8-10-membered C₄₋₉heterocycloalkyl, comprising one tofour heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a bicyclic 8-10-membered C₅₋₉heterocycloalkyl, comprising one tothree nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ia), or (Ib)disclosed herein:

L¹ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is monocyclic or bicyclic 5-10-membered C₄₋₉heteroaryl, comprisingone to three heteroatoms, each independently selected from nitrogen,oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is monocyclic or bicyclic 5-9-membered C₄-₈heteroaryl, comprising oneto three heteroatoms, each independently selected from nitrogen, oxygen,and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 5-6-membered C₃₋₅heteroaryl, comprising one to threeheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 6-membered C₄₋₅heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 5-membered C₃₋₄heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic or bicyclic 3-15-membered C₂₋₁₄heterocycloalkyl

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic or bicyclic 3-10-membered C₂₋₉heterocycloalkyl,comprising one to four heteroatoms, each independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a bicyclic 8-10-membered C₄₋₉heterocycloalkyl, comprising one tofour heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ib), (Iba), or(Ibb) disclosed herein:

L² is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is monocyclic or bicyclic 5-10-membered C₄-₉heteroaryl, comprisingone to three heteroatoms, each independently selected from nitrogen,oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is monocyclic or bicyclic 5-9-membered C₄-₈heteroaryl, comprising oneto three heteroatoms, each independently selected from nitrogen, oxygen,and sulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 5-6-membered C₃₋₅heteroaryl, comprising one to threeheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 6-membered C₄₋₅heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 5-membered C₂₋₄heteroaryl, comprising one to threeheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic or bicyclic 3-15-membered C₂₋₁₄heterocycloalkyl

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a bicyclic 8-10-membered C₄₋₉heterocycloalkyl, comprising one tofour heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ia), (Ib),(Iba), or (Ibb) disclosed herein:

L³ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic 5-membered C₃₋₄heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma bicyclic or tricyclic 9-15-membered C₈₋₁₄heterocycloalkyl, comprisingone to three heteroatoms, each independently selected from nitrogen,oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic or bicyclic 3-10-membered C₂₋₉heterocycloalkyl, comprisingone to four heteroatoms, each independently selected from nitrogen,oxygen, and sulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma bicyclic 8-10-membered C₄₋₉heterocycloalkyl, comprising one to fourheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma bicyclic 8-10-membered C₅₋₉heterocycloalkyl, comprising one to threenitrogen atoms.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic 4-7-membered C₃₋₆₋heterocycloalkyl, comprising one to twonitrogen atoms.

In some embodiments of a chemical entity of Formula (I) or (Ic)disclosed herein:

L⁴ and L⁵ come together with the nitrogen to which they attached to forma monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one to twonitrogen atoms.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb) or (Icc) disclosed herein:

L⁶ is a monocyclic 5-6-membered C₃₋₅heteroaryl, comprising one to threeheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb) or (Icc) disclosed herein:

L⁶ is a monocyclic 6-membered C₄₋₅heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb) or (Icc) disclosed herein:

L⁶ is a monocyclic 5-membered C₃₋₄heteroaryl, comprising one to twoheteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb) or (Icc) disclosed herein:

L⁶ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo heteroatoms, each independently selected from nitrogen, oxygen, andsulfur.

In some embodiments of a chemical entity of Formula (I), (Ic), (Icaa),(Icab), (Icb) or (Icc) disclosed herein:

L⁶ is a monocyclic 5-6-membered C₃₋₅₋heterocycloalkyl, comprising one totwo nitrogen atoms.

In some embodiments, a chemical entity is selected from compounds ofExamples 1-814, and all pharmaceutically acceptable forms thereof,including pharmaceutically acceptable chelates, solvates, conformers,crystalline forms/polymorphs, salts, prodrugs, and pharmaceuticallyactive metabolites. In other embodiments, a chemical entity is selectedfrom compounds of Examples 1-814 and pharmaceutically acceptable saltsthereof. In still other embodiments, a chemical entity is a compoundselected from Examples 1-814.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), tautomers of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I), andpharmaceutically active metabolites of compounds of Formula (I).

Isotopically-Labeled Compounds

Compounds of Formula (I) may include any isotope where one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. Forexample, the isotopes may be isotopes of carbon, chlorine, fluorine,hydrogen, iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium,including ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and all forms of such compounds,such as pharmaceutically acceptable salts) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentembodiments are useful in binding affinity studies, as well as drug andsubstrate tissue distribution and target occupancy assays. For example,isotopically labeled compounds are particularly useful in SPECT (singlephoton emission computed tomography) and in PET (positron emissiontomography), as discussed further herein. In addition, isotopicallylabelled compounds are useful for improving the absorption,distribution, metabolism and/or excretion (ADME) properties of drugs.For instance, replacement of one or more hydrogen atoms with deuterium(²H) can modify the metabolism of a drug and improve the metabolicprofile by decreasing the metabolic clearance in vivo, extending thehalf-life, reducing C_(max) or reducing levels of potentially toxicmetabolites.

COMPOSITIONS

In some embodiments, the chemical entities disclosed herein, and moreparticularly, compounds and pharmaceutically acceptable salts thereof,are used, alone or in combination with one or more additional activeingredients, to formulate pharmaceutical compositions.

In some embodiments, a pharmaceutical composition can comprise: (a) aneffective amount of at least one chemical entity of the presentdisclosure; and (b) a pharmaceutically acceptable carrier.

In some embodiments, a pharmaceutical composition comprises a compound,or pharmaceutically acceptable salt thereof, of any of the embodimentsand examples disclosed herein; and a pharmaceutically acceptablecarrier. In specific embodiments, a pharmaceutical composition comprisesa compound of any one of Examples 1-814; and a pharmaceuticallyacceptable carrier.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington’s Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Dosage Forms

The chemical entities, and more particularly, compounds andpharmaceutically acceptable salts thereof, may be systemicallyadministered, e.g., orally, in combination with a pharmaceuticallyacceptable vehicle such as an inert diluent or an assimilable ediblecarrier. They may be enclosed in hard or soft shell gelatin capsules,may be compressed into tablets, or may be incorporated directly with thefood of the patient’s diet. For oral therapeutic administration, theactive compound may be combined with one or more excipients and used inthe form of ingestible tablets, buccal tablets, troches, capsules,elixirs, suspensions, syrups, wafers, and the like. Such compositionsand preparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be in a range from 1% to 65% or 2 to 60% ofthe weight of a given unit dosage form. The amount of active compound insuch therapeutically useful compositions is such that an effectivedosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid. These compositions and formulationscan be prepared according to ordinary skill in the art.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the chemical entities and compounds (active agents) ofthe present disclosure can be determined by comparing their in vitroactivity and in vivo activity in animal models. Methods for theextrapolation of effective dosages in mice, and other animals, to humansare known to the art. Useful dosages of the compounds of formula I canbe determined by comparing their in vitro activity, and in vivo activityin animal models. Methods for the extrapolation of effective dosages inmice, and other animals, to humans are known to the art (e.g., U.S. Pat.No. 4,938,949).

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject’s previous or ongoing therapy, thesubject’s health status and response to drugs, concomitant medications,and the judgment of the treating physician. An exemplary dose can be inthe range from 0.0001 to 200 mg of active agent per day, from 0.001 to200 mg per day, from 0.05 to 100 mg per day, from 0.1 to 10 mg/day, from1 to 200 mg/day, or from 5 to 50 mg/day.

In some embodiments, the desired dose may be presented in a unit dosageform; for example, a composition containing from 0.01 to 1000 mg, from0.1 to 200 mg, from 0.5 to 100 mg, or from 1 to 50 mg, of activeingredient per unit dosage form.

In other embodiments, the desired dose may be presented in divided dosesadministered at appropriate intervals, for example, as two, three, four,or more sub-doses per day. (e.g., BID, TID, QID). The sub-dose itselfmay be further divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

METHODS AND USES Uses of Isotopically-Labeled Compounds

In some embodiments, the present disclosure provides methods of usingisotopically labeled compounds of the present invention in: (i)metabolic studies (with, for example, ¹⁴C), and reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) radioactive treatment of patients.

Isotopically labeled compounds and related chemical entities of Formula(I) can generally be prepared by carrying out the procedures disclosedin the schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Compounds labeled with ¹⁸F or ¹¹C maybe particularly preferred for PET, and an ¹²³I-labeled compound may beparticularly preferred for SPECT studies. Further substitution ofcompounds of Formula (I) with heavier isotopes such as deuterium (i.e.,²H) may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements.

THERAPEUTIC METHODS Generally

Chemical entities and compositions of the present disclosure are usefulin various therapeutic methods (or in the manufacture of a medicamentfor use in such methods), comprising administering to a subject in needthereof a chemical entity or composition herein. In a specific aspect,the chemical entity is a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof. More particularly, the chemical entity is acompound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab),(Icb), or (Icc), or a pharmaceutically acceptable salt thereof.

Such therapeutic methods can be directed to a wide range of indications,as described further herein, including cognitive or motor deficitsassociated with neurological disorders, neurodegenerative disorders,immunological and inflammatory disorders, and numerous peripheraldisorders.

In some embodiments, chemical entities and compositions herein areuseful in methods of inhibiting PDE1 activity, comprising exposing PDE1to an effective amount of a chemical entity or composition of any one ofthe embodiments disclosed herein. In some embodiments, the PDE1 is in ananimal, and more particularly, is in a human subject.

In some embodiments, chemical entities and compositions herein areuseful in methods of treating a subject suffering from or diagnosed witha disorder mediated by PDE1 activity, comprising administering to asubject in need thereof an effective amount of a chemical entity orcomposition of any one of the embodiments herein. In one aspect, thesubject is diagnosed with a disorder mediated by PDE1 activity. Inanother aspect, the subject is suffering from a disorder mediated byPDE1 activity.

In some embodiments, chemical entities and compositions herein areuseful in methods of enhancing neuronal plasticity, an essentialproperty of the brain that can be impaired in numerous CNS disorders andaugmented in healthy animals. Without being limited by mechanism, suchchemical entities can enhance cyclic adenosine monophosphate (cAMP)response element binding protein (CREB) pathway function in cells,modulating transcription of multiple genes involved in synapticplasticity (See, e.g., Tully et al., 2003, Nat. Rev. Drug Discov. 2,267-277; Alberini, 2009, Physiol. Rev. 89, 121-145; Medina, 2011, Front.Neurosci. 5, 21). Accordingly, in some embodiments, the presentdisclosure provides methods of enhancing neuronal plasticity, comprisingadministering to a subject in need thereof an effective amount of achemical entity or composition of any one of the embodiments herein. Inspecific embodiments, chemical entities of the present disclosure areuseful in methods of enhancing cognitive or motor function, comprisingadministering to a subject in need thereof an effective amount of achemical entity or composition of any one of the embodiments disclosedherein.

In some embodiments, chemical entities and compositions herein are usedas neuroprotective agents, for example, by enhancing neuronal growth andsurvival. Accordingly, the present disclosure provides methods ofconferring neuroprotection, comprising administering to a subject inneed thereof an effective amount of a chemical entity or compositiondescribed herein.

In some embodiments, chemical entities and compositions herein are usedas agents to promote neurogenesis, which may be applicable to treatingneurological disorders, as described further herein. PDE1B is highlyexpressed in the dentate gyrus and olfactory bulb, the two areas whereneurogenesis occurs in the adult nervous system. Neurogenesis in thehippocampus has been implicated in memory formation in depression, andin cognitive deficits underlying neuropsychiatric disease, including,but not limited to, PTSD and other anxiety disorders. See, e.g., Shorset al., 2001, Nature 410, 372-376; Shors et al., 2004, Trends Neurosci.27, 250-256; Ming and Song, 2011, Neuron 70, 687-702; Hill et al., 2015,Neuropsychopharmacology 40, 2368-2378; Kheirbek et al., 2012, Nat.Neurosci. 15, 1613-1620.

In some embodiments, chemical entities and compositions herein are usedas treating disorders that include aberrant or dysregulated signalingpathways mediated by PDE1. Such PDE1-related signaling pathways include,but are not limited to, those involving nitric oxide, natriureticpeptides (e.g., ANP, BNP, CNP), dopamine, noradrenalin, neurotensin,cholecystokinin (CCK), vasoactive intestinal peptide (VIP), serotonin,glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine,adenosine (e.g., A2A receptor), cannabinoids, natriuretic peptides(e.g., ANP, BNP, CNP), and endorphins.

In a specific aspect, they are useful in modulating dopaminergicsignaling or treating disorders characterized by alterations in dopaminesignaling, particularly dopaminergic signaling mediated by the dopaminereceptor D1, which in humans is encoded by the DRD1 gene. See, e.g.,Nishi and Snyder, 2010, J. Pharmacol. Sci.114, 6-16.

In some embodiments, chemical entities and compositions are used as“agents” (or “augmenting agents”) to increase the efficiency of trainingprotocols that facilitate functional reorganization in targeted“domains” (or “functions”) in the brain.

In some embodiments, chemical entities and compositions are used incombination with other therapies or with other active agents, asdescribed further herein.

Neurological Disorders

In some embodiments the present disclosure provides methods of treatingneurological disorders, comprising administering to a subject in needthereof a chemical entity or composition described herein. In a specificaspect, the chemical entity is a compound of Formula (I) or apharmaceutically acceptable salt thereof. More particularly, thechemical entity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb),(Icaa), (Icab), (Icb), or (Icc), or a pharmaceutically acceptable saltthereof.

In some embodiments, the method is directed to a neurological impairment(“neurological deficit”) associated with the neurological disorder,including a cognitive impairment (“cognitive deficit”) or a motorimpairment (“motor deficit”) associated with the pathology of theneurological disorder.

A cognitive impairment can manifest, for example, as a deficit in:attention (e.g., sustained attention, divided attention, selectiveattention, processing speed); executive function (e.g., planning,decision, and working memory); memory (e.g., immediate memory; recentmemory, including free recall, cued recall, and recognition memory; andlong-term memory, which can be divided into explicit memory (e.g.,declarative memory), such as episodic, semantic, and autobiographicalmemory, and into implicit memory (e.g., procedural memory)); expressivelanguage, including naming, word recall, fluency, grammar, and syntax;understanding speech or writing (e.g., aphasia); perceptual-motorfunctions (e.g., abilities encompassed under visual perception,visual-constructional, perceptual-motor praxis, and gnosis); and socialcognition (e.g., recognition of emotions, theory of mind). In certainembodiments, the cognitive deficit is a deficit in memory and moreparticularly, a deficit in long-term memory.

A motor impairment can manifest, for example, as weakness or paralysis,deficits in upper and lower extremity function, problems with balance orcoordination, impairments of gross motor skills, and deficits in finemotor skills.

A neurological disorder (or condition or disease) is any disorder of thebody’s nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, and the primary type of cause. The broadestdivision is between disorders of the central nervous system (CNS), whichcomprises the nerves in the brain and spinal cord, and disorders of theperipheral nervous system (PNS), which comprises the nerves outside thebrain and spinal cord.

Many CNS disorders are amenable for treatment with chemical entities andcompositions, including those discussed herein. As used herein, theterms “Neurodevelopment disorders,” “Schizophrenia spectrum and otherpsychotic disorders,” “Bipolar and related disorders,” “Depressivedisorders,” “Anxiety disorders,” “Obsessive-compulsive and relateddisorders,” “Dissociative disorders,” “Disruptive, impulse-control, andconduct disorders,” “Trauma- and stressor-related disorders,” “Feedingand eating disorders,” “Sleep disorders,” “Sexual disorders,”“Substance-related and addictive disorders,” “Personality disorders,”“Somatic symptom disorders,” “Neurodegenerative disorders,”“Neurocognitive disorders,” “Delirium,” “Dementias,” and “Age-associatedcognitive deficits, include the diagnosis and classification of theseCNS conditions and disorders (and related CNS conditions and disorders)as described in the Diagnostic and Statistical Manual of MentalDisorders (DSM-5; 5^(th) ed., 2013, American Psychiatric Association).The skilled artisan will recognize that there are alternativenomenclature and classification systems for these CNS disorders, andthat these systems evolve with medical and scientific progress. Thus,these terms in this paragraph are intended to include like disordersthat are described in other diagnostic sources.

Mental and Psychiatric Disorders

In certain embodiments, chemical entities and compositions herein areuseful in treating mental or psychiatric disorders, and moreparticularly, a cognitive impairment associated with the pathology ofsuch disorders. In a specific aspect, the chemical entity is a compoundof Formula (I), or pharmaceutically acceptable salt thereof. Moreparticularly, the chemical entity is a compound of Formula (Ia), (Ib),(Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

Mental and psychiatric disorders are well known in the art, and include,but are not limited to, one or more of the following:

-   Neurodevelopmental (or “developmental” disorders), such as    intellectual disability disorders (e.g., Rubinstein-Taybi syndrome,    Down syndrome and Fragile X syndrome); communication disorders;    autism-spectrum disorders; attention-deficit/hyperactivity    disorders; specific learning, language, or reading (e.g., dyslexia)    disorders; motor disorders; fetal alcohol spectrum disorders (FASD);    and other neurodevelopmental disorders;-   Schizophrenia spectrum and other psychotic disorders, such as    schizophrenia, schizotypal (personality) disorder, delusional    disorder, brief psychotic disorder, schizoaffective disorder,    substance/medication-induced psychotic disorder, psychotic disorder    due to another medical condition, catatonia, catatonia associated    with another mental disorder (catatonia specifier), catatonic    disorder due to another medical condition, unspecified catatonia,    schizophreniform disorder, and other schizophrenia spectrum and    psychotic disorders;-   Bipolar and related disorders, such as Bipolar I and II disorders,    cyclothymic disorders, and other bipolar and related disorders;-   Depressive disorders, such as major depressive disorder, persistent    depressive disorder (dysthymia), a major depressive episode of the    mild, moderate, or severe type, a depressive episode with    melancholic features, a depressive episode with catatonic features,    seasonal depression (seasonal affective disorder), disruptive mood    dysregulation disorder, premenstrual dysphoric disorder,    substance/medication-induced depressive disorder, depressive    disorder due to another medical condition, mood disorders due to a    general medical conditions, and other depressive disorder;-   Anxiety disorders, such as specific phobia, agoraphobia, social    anxiety disorder (social phobia), panic attack, panic disorder,    acute stress disorder, generalized anxiety disorder, posttraumatic    stress disorder (PTSD), and other anxiety disorders;-   Obsessive-compulsive and related disorders, such as    obsessive-compulsive disorder (OCD), body dysmorphic disorder,    hoarding disorder, trichotillomania (hair-pulling disorder),    excoriation (skin-picking) disorder, substance/medication-induced    obsessive-compulsive and related disorder, obsessive-compulsive and    related disorder due to another medical condition, and other    specified obsessive-compulsive and related disorder and unspecified    obsessive-compulsive and related disorder (e.g., body-focused    repetitive behavior disorder, obsessional jealousy), and other    obsessive-compulsive and related disorders;-   Dissociative disorders, such as dissociative identity disorder,    dissociative amnesia, depersonalization/derealization disorder,    dissociative subtypes (in conjunction with other disorders), and    other dissociative disorders;-   Disruptive, impulse-control, and conduct disorders, such as conduct    disorder, antisocial personality disorder, pyromania, kleptomania,    and other disruptive, impulse-control, and conduct disorders;-   Trauma- and stressor-related disorders, such as reactive attachment    disorder, disinhibited social engagement disorder, posttraumatic    stress disorder, acute stress disorder, adjustment disorders, and    other trauma- and stressor-related disorders;-   Feeding and eating disorders, such as pica, rumination disorder,    avoidant/restrictive food intake disorder, anorexia, bulimia,    binge-eating disorder, and other feeding and eating disorders;-   Sleep disorders, such as sleep-wake disorders, insomnia disorder,    hypersomnolence disorder, narcolepsy, breathing-related sleep    disorders, sleep apnea, circadian rhythm sleep-wake disorders,    non-rapid eye movement (NREM) sleep arousal disorders, nightmare    disorder, rapid eye movement (REM) sleep behavior disorder, restless    legs syndrome, and substance/medication-induced sleep disorder,    parasomnias, and other sleep-wake disorders;-   Sexual disorders, such as arousal disorders, desire disorders,    dysfunctions, substance- and medication-induced dysfunctions,    impotence and other sexual disorders;-   Substance-related and addictive disorders, such as those involving    alcohol, drugs, stimulants, opioids, tobacco, and    non-substance-related addictive disorders; and other    substance-related and addictive disorders;-   Personality disorders, such as antisocial personality disorder,    borderline personality disorder, histrionic personality disorder,    narcissistic personality disorder, avoidant personality disorder,    dependent personality disorder, obsessive-compulsive personality    disorder, paranoid personality disorder, schizoid personality    disorder, schizotypal personality disorder, personality change due    to another medical condition, and other personality disorders; and-   Somatic symptom and related disorders, such as somatic symptom    disorder, illness anxiety disorder (hypochondriasis), factitious    disorder, factitious disorder imposed on another, pain disorders,    conversion disorder, and other somatic symptom and related    disorders.

Schizophrenia

In specific embodiments, the mental or psychiatric disorder is aschizophrenia spectrum or psychotic disorder, and, in particular, isschizophrenia. Schizophrenia is a devastating neurological disorder,characterized by a combination of symptoms, which may include negative,positive, or cognitive symptoms. Negative symptoms can include flataffect (lack or decline in emotional response), alogia (lack or declinein speech), avolition (lack or decline in motivation), anhedonia (theinability to experience pleasure from activities usually foundenjoyable), and asociality (lack of motivation to engage in socialinteraction, or a preference for solitary activities). Positive symptomsinclude paranoia, hallucinations, and delusions. Cognitive symptoms caninclude impairments in such functions as attention, memory, reasoning,and processing speed. See, e.g., Keefe and Harvey, 2012, Handb. Exp.Pharmacol. 213, 11-23. Intracellular signaling of dopamine D1 andvarious serotonin receptors, which signal through cyclic nucleotides, isknown to be defective in schizophrenia, as well as depression and othercognitive disorders. More generally, PDEs, include PDE1, have beenimplicated at the interface between cognitive deficits andneuropsychiatric disorders. See, e.g., Wang et al., 2015, Curr. Pharm.Des. 21, 303-316.

Accordingly, the present disclosure provides a method of treatingschizophrenia, comprising administering to a subject in need thereof aneffective amount of a chemical entity or composition herein. In aspecific aspect, the chemical entity is a compound of Formula (I), orpharmaceutically acceptable salt thereof. More particularly, thechemical entity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb),(Icaa), (Icab), (Icb), or (Icc), or a pharmaceutically acceptable saltthereof. In some embodiments, the treatment is directed to a positivesymptom of schizophrenia. In some embodiments, treatment is directed toa negative symptom of schizophrenia. In some embodiments, treatment isdirected to cognitive impairment associated with schizophrenia (CIAS).In some embodiments, the treatment also include a cognitive trainingprotocol.

Addictive Disorders

In specific embodiments, the mental or psychiatric disorder is anaddictive disorder. In one aspect, the subject is addicted to anaddictive agent selected from the group consisting of alcohol, nicotine,marijuana, a marijuana derivative, an opioid agonist (such as morphine,methadone, fentanyl, sufentanil, or heroin), a benzodiazepine, abarbiturate, and a psychostimulant, such as cocaine or amphetamine. Inanother aspect, the addiction is associated with an obsessive-compulsivedisorder. In another aspect, the disorder is associated with a primaryimpulse-control disorder, such as binge eating, pathological gambling,addiction to pornography, sex addiction, compulsive spending, anorexia,bulimia, kleptomania, pyromania, trichotillomania, compulsiveover-exercising, or compulsive overworking.

Accordingly, the present disclosure provides a method of treating anaddictive disorder, comprising administering to a subject in needthereof an effective amount of a chemical entity or composition herein.In a specific embodiment, the chemical entity is a compound of Formula(I), or pharmaceutically acceptable salt thereof. More particularly, thechemical entity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb),(Icaa), (Icab), (Icb), or (Icc), or a pharmaceutically acceptable saltthereof.

Cognitive Disorders

In specific embodiments, the present disclosure provides a method oftreating a cognitive disorder, and more particularly, a neurologicalimpairment associated with the disorder, comprising administering to asubject in need thereof an effective amount of a chemical entity orcomposition described herein. In a specific aspect, the chemical entityis a compound of Formula (I), or pharmaceutically acceptable saltthereof. More particularly, the chemical entity is a compound of Formula(Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

A “cognitive disorder” (or “neurocognitive disorder”) is one in whichthe primary clinical feature is impaired cognition, i.e., a disorder inwhich the primary cognitive deficit has not been present since birth orvery early life and therefore represents a decline from a previouslyattained level of functioning. Such disorders, include one or more ofthe following:

-   Delirium, such as substance-intoxication (or withdrawal) delirium,    medication-induced delirium, and other forms of delirium;-   Dementias and other cognitive impairments due to acquired diseases,    such as HIV infection, or transmissible encephalopathies; or due to    neurodegenerative or progressive nervous system diseases, such as    Alzheimer’s disease, Parkinson’s disease (in particular Parkinson’s    Disease Dementia (PDD)), Huntington’s disease, Lewy body disease,    Pick’s disease, a prion disease (e.g., Creutzfeldt-Jakob disease),    Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),    frontotemporal lobar degeneration (FTLD), and corticobasal    degeneration; dementia due to a vascular disease (“vascular    disease”); autoimmune disorders; and other dementias and    neurodegenerative diseases.-   Age-associated cognitive decline, including age-associated memory    impairment (AAMI), also referred to as age-related memory impairment    (AMI) (See, e.g., Crook et al., 1986, Devel. Neuropsychol. 2,    261-276); and cognitive decline affecting patients in early stages    of cognitive decline, as in Mild Cognitive Impairment (MCI) (See,    e.g., Arnáiz and Almkvist, 2003, Acta Neurol. Scand. Suppl. 179,    34-41);-   Trauma-dependent losses of function, including vascular diseases,    such as stroke (e.g., ischemic or hemorrhagic stroke) or ischemia;    infarction, including cerebral and myocardial; microvascular or    macrovascular disease arising from diabetes or arthrosclerosis;    traumatic brain injury (TBI), such as brain trauma including    subdural hematoma and brain tumor; head trauma (closed and    penetrating); head injury; tumors, such as nervous system cancers,    including cerebral tumors affecting the thalamic or temporal lobe;    hypoxia, and viral, fungal, or bacterial infection (e.g.,    encephalitis, or meningitis); excitotoxicity; and seizures; and-   Cognitive impairments due to chemotherapy, such as post-chemotherapy    cognitive impairments (PCCI); chemotherapy-induced cognitive    dysfunction or impairments; chemo brain; or chemo fog.

Such cognitive disorders can include neurological impairments other thancognitive impairments. For example, trauma-dependent losses of function,such as stroke, traumatic brain injury, head trauma, and head injury,can include impairments in multiple neurological functions, such asimpairments in motor functions.

Age Associated Cognitive Decline

In specific embodiments, the cognitive disorder is age-associatedcognitive decline.

In one aspect, the age-related cognitive decline is age-associatedmemory impairment (AAMI). AAMI is a decline in various cognitiveabilities, in particular memory abilities, associated with normal aging.For example, AAMI subjects show a decline in the ability to encode newmemories of events or facts, as well as in working memory (Hedden andGabrieli, 2004, Nat. Rev. Neurosci. 5, 87-96). In addition, AAMIsubjects, when compared with age-matched controls, appeared to beimpaired in tests of executive functions associated with frontal lobefunction. These and other studies suggest an important role for frontallobe dysfunction in the memory loss of elderly people (Nilsson, 2003,Acta Scand. Suppl. 179, 7-13). In general, an AAMI diagnosis identifiespersons with subjectively and objectively evidenced memory loss withoutcognitive decline impaired enough to warrant the diagnosis of dementia.For example, the NIH working group has established multiple criteria fora diagnosis of AAMI in a person aged 50 or older, including the presenceof subjective memory decline, objective evidence of memory loss,evidence of adequate intellectual function, and the absence of dementia(or other memory-affecting disease) (Crook et al., 1986, Devel.Neuropsychol. 2, 261-276). Individuals with AAMI have been shown to havea three-fold greater risk for development of dementia than individualswho do not meet AAMI criteria (Goldman and Morris, 2002, Alzheimer Dis.Assoc. Disord. 75, 72-79).

In another aspect, the age-associated cognitive decline is MildCognitive Impairment, which may be diagnosed when an individual’s memorydeclines below the level considered normal for that age group. In otherwords, MCI is a condition in which people face memory problems moreoften than that of the average person their age. Symptoms often includemisplacing items, forgetting events or appointments, and having troublethinking of desired words (e.g., Arnáiz and Almkvist, 2003, Acta Neurol.Scand. Suppl. 179, 34-41). MCI can represent a transitional statebetween cognitive changes of normal aging and Alzheimer’s disease (AD).Many people who experience mild cognitive impairment are at a high riskof developing Alzheimer’s disease. About 12% of people aged 65 or olderdiagnosed with MCI go on to develop Alzheimer’s disease within a year,and about 40% develop Alzheimer’s within three years. This is a muchhigher rate than in the general population, in which only about 1% ofpeople aged 65 or older develop Alzheimer’s each year. Thus, people withMCI are considered at heightened risk to develop Alzheimer’s disease.Some patients with MCI, however, never progress to AD.

Accordingly, the disclosure includes methods of treating age-associatedcognitive decline, and more particularly, age-related memory impairmentor mild cognitive impairment, comprising administering to a subject inneed thereof an effective amount of a chemical entity or compositiondisclosed herein. In a specific aspect, the chemical entity is acompound of Formula (I), or pharmaceutically acceptable salt thereof.More particularly, the chemical entity is a compound of Formula (Ia),(Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

Trauma-Dependent Loss of Function

In specific embodiments, the cognitive disorder is a trauma-dependentloss of function, and more particularly, stroke or TBI. Accordingly, thedisclosure includes methods of treating a trauma-dependent loss offunction, and more particularly, stroke or TBI, comprising administeringto a subject in need thereof an effective amount of a chemical entity orcomposition disclosed herein.

Movement Disorders

In certain embodiments, the present disclosure provides methods oftreating movement and motor disorders, and more particularly, a movementor motor impairment associated with the pathology of such disorders,comprising administering to a subject in need thereof an effectiveamount of a chemical entity or composition described herein. In aspecific aspect, the chemical entity is a compound of Formula (I), orpharmaceutically acceptable salt thereof. More particularly, thechemical entity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb),(Icaa), (Icab), (Icb), or (Icc), or a pharmaceutically acceptable saltthereof.

Loss of dopaminergic neurotransmission in striatum is a central cause ofneurodegenerative diseases leading to movement disorders, such asParkinson’s disease and Huntington’s disease. See, e.g., Sasaki et al.,2004, J. Neurochem. 89, 474-483; Morales-Garcia et al., 2014, Neurobiol.Aging. 36, 1160-1173; Banerjee et al., 2012, Bioorg. Med. Chem. Lett.22, 6286-6291. PDE1 is highly expressed in the striatum, and growingamount of evidence suggest that phosphodiesterases play a critical rolein modulating dopamine signaling in the brain (Ramirez and Smith, 2014,Cent. Nerv. Syst. Agents Med. Chem. 14, 72-82).

Movement disorders include, but are not limited to, basal gangliadisorders, Parkinson’s disease, Post-Encephalitic Parkinsonism,Dopamine-Responsive Dystonia, Hallervorden-Spatz Syndrome (HSS),Restless Leg Syndromes, Wilson’s Disease, Shy-Drager Syndrome, PeriodicLimb Movement Disorder (PLMD), Periodic Limb Movements in Sleep (PLMS),Tourette’s Syndrome, Restless Leg(s) Syndrome (RLS); chorea, such asthat in Huntington’s disease; myoclonus (including generalized myoclonusand focal myoclonus); tics (including simple tics, complex tics andsymptomatic tics); and hyperkinetic, hypokinetic, and dyskineticdisorders; movement disorders induced by drugs, diseases associated withstriatal hypofunction; and other movement and motor disorders.

In specific embodiments, the dyskinetic disorder is a drug-induceddyskinesia. More particularly, the dyskinetic disorder is levodopainduced dyskinesia (LID) or tardive dyskinesia (TD), which represent themost common forms of drug-induced dyskinesias. For example, uncontrolledstimulation of supersensitized dopamine D1 receptors in the directstriatonigral pathway are thought to mediate LIDs. In addition,long-term blockade of dopamine D2 receptors in the basal ganglia bydopamine D2 antagonists (e.g., neuroleptics) may produce compensatorysupersensitivity of dopamine receptors and TD. Accordingly, in specificembodiments, then present disclosure provides methods of treating LID(or TD), comprising administering to a subject in need therefor aneffective amount of a chemical entity of any of the embodimentsdisclosed herein.

In certain embodiments, the movement disorder is a basal gangliadisorder.

In other embodiments, the movement disorder includes kinesias andakinetic-rigid syndromes, such as Parkinson’s disease or corticobasaldegeneration; Tourette’s syndrome, epilepsy, muscular spasms, anddisorders associated with muscular spasticity or weakness; dyskinesias,including tremors, such as rest tremor, postural tremor and intentiontremor.

In specific embodiments, the movement disorder is Parkinson’s disease orHuntington’s disease, as discussed further herein.

In some embodiments, the methods are directed to a specific movementabnormality associated with the pathology of a movement or motordisorder. Movement abnormalities include, but are not limited to,tremors, resting tremors, rigidity, bradykinesia, and deficient posturalreflexes.

Neurodegenerative Disorders

In specific embodiments, the disclosure provides methods of treating aneurodegenerative disorder, and more particularly treating aneurological impairment associated with the pathology of aneurodegenerative disorder, comprising administering to a subject inneed thereof an effective amount of a chemical entity or compositiondescribed herein.

Neurodegenerative disorders can result from a primary nervous systemdisease or a primary nervous system injury. Chronic neuroinflammation isa hallmark of neurodegenerative disorders, and in animal and cellularmodels, PDE1 inhibition shows neuroprotective and anti-inflammatoryeffects that are expected to be beneficial in treating neuroinflammationand other hallmarks of such disorders.

Accordingly, in some embodiments, the therapeutic methods are directedto neurodegenerative disorders resulting from a primary nervous systemdisease. Such diseases include, but are not limited to, Parkinson’sdisease, Alzheimer’s disease, Huntington’s disease, Lewy body disease,Pick’s disease, a prion disease (e.g., Creutzfeldt-Jakob disease),Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),frontotemporal lobar degeneration (FTLD), and corticobasal degeneration.

In other embodiments, the therapeutic methods are directed to aneurodegenerative disorder resulting from a primary nervous systeminjury. Such primary injuries can include, but are not limited to,stroke, including hemorrhagic stroke and ischemic stroke; a traumaticbrain injury (TBI), which can include closed head injuries and blunttrauma, including those caused by participation in sports, andpenetrating trauma, such as gunshot wounds; spinal cord injuries;glaucoma, cerebral ischemia, or damages caused by surgery such as tumorexcision.

Parkinson’s Disease

In specific embodiments, the present disclosure provides methods oftreating Parkinson’s disease, comprising administering to a subject inneed thereof an effective amount of a chemical entity or compositiondescribed herein. Parkinson’s disease (PD), also known as Parkinson’s,idiopathic Parkinsonism, or primary Parkinsonism, is a degenerativedisorder of the CNS estimated to afflict more than 5 million peopleworldwide. It is a slowly progressive neurological condition,characterized by tremors, stiffness, slowness of movement (bradykinesia)and impaired balance. Altered cAMP/cGMP levels are associated withParkinson’s disease, and PDE1B activity is increased in models ofParkinson’ disease (Sancesario et al., 2004, Eur. J. Neurosci. 20,989-1000).

While Parkinson’s disease has been defined by its motor hallmarks,non-motor features such as cognitive impairment and dementia have beenincreasingly recognized. For example, MCI is common in a significantfraction (with estimates ranging from 20%-50%) of non-demented PDpatients. See, e.g., Broeders et al., 2013, Neurology 81, 346-352. Whilediagnostic criteria are not completely uniform, PD patients with MCI(PD-MCI patients) typically exhibit non-amnestic deficits in cognitivedomains such as executive function, attention, and visuospatial function(Litvan et al., 2012, Mov. Disord. 27, 349-356). The cognitive phenotypeof PD-MCI is heterogeneous, however, with some patients demonstratingamnestic deficits. Certain PD-MCI patients may be at high risk fordeveloping dementia. (e.g., Goldman and Litvan, 2011, Minerva Med. 102,441-459).

Thus, in specific embodiments, chemical entities and compositions hereincan be used to treat motor deficits associated with PD, and in otherembodiments to treat cognitive impairments associated with PD, includingin PD-MCI subjects. In a specific aspect, the chemical entity is acompound of Formula (I), or pharmaceutically acceptable salt thereof.More particularly, the chemical entity is a compound of Formula (Ia),(Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

Alzheimer’s Disease

In specific embodiments, the present disclosure provides methods oftreating Alzheimer’s disease (AD), comprising administering to an animalin need thereof an effective amount of a chemical entity or compositiondisclosed herein. In a specific aspect, the chemical entity is acompound of Formula (I), or pharmaceutically acceptable salt thereof.More particularly, the chemical entity is a compound of Formula (Ia),(Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

Alzheimer’s disease is a neurodegenerative disorder that involves theprogressive loss of memory and other cognitive functions. Although thepathogenesis of AD is not well known, its etiology is associated withthe presence of P-amyloid (or senile) plaques; deficiencies inneurotransmission; loss of neurons, especially in the cortex andhippocampus; neurofibrillary tangles; and the hyperphosphorylation andintraneuronal deposition of the microtubule-associated protein tau inthe form of filaments; intraneuronal deposition of aggregated taufilaments. In Alzheimer’s accumulation of the amyloid-β protein may leadto a reduction on CREB phosphorylation, which may be related to thecognitive deficits seen in this condition, and more generally,increasing cAMP or cGMP levels by PDE4 inhibition can restore neuronalplasticity in Alzheimer models (Vitolo et al., 2002, Proc. Natl. Acad.Sci. U.S.A. 99, 13217-13221; Medina, 2011, Front. Neurosci. 5, 21).

Huntington’s Disease

In specific embodiments, the disclosure provides a method of treatingHuntington’s disease (or “Huntington’s chorea”), comprisingadministering to a subject in need thereof an effective amount of achemical entity or chemical entity disclosed herein. In a specificaspect, the chemical entity is a compound of Formula (I), orpharmaceutically acceptable salt thereof. More particularly, thechemical entity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb),(Icaa), (Icab), (Icb), or (Icc), or a pharmaceutically acceptable saltthereof.

There are two forms of Huntington’s disease: adult-onset Huntington’sdisease, which is the most common form and usually begins in subjectsaged in the mid 30′s and 40′s, and early-onset Huntington’s disease,which accounts for a small number of cases and begins in childhood oradolescence. Symptoms of Huntington’s disease include behavioralchanges, abnormal and unusual movements, and worsening dementia (e.g.,Dumas et al., 2013, Front. Biosci. (Schol. Ed) 5, 1-18). Huntington’sdisease (HD, or Huntington chorea) is a genetic disorder, whosepathology includes degeneration of striatal neurons in the basal gangliaresponsible for movement and coordination. PDE1 is highly expressed inthe striatum, and PDE1 inhibition has been shown to confer protectionagainst behavioral and biochemical toxicities in an experimental modelsof Huntington’s disease (Gupta and Sharma, 2014, Eur. J. Pharmacol. 732,111-122). A detailed set of criteria for the diagnosis of Huntington’sdisease is set forth in the Diagnostic and Statistical Manual of MentalDisorders (DSM-5; 5^(th) ed., 2013, American Psychiatric Association).

Augmented Training

In some embodiments, chemical entities, and compositions thereof, of thepresent disclosure are used as augmenting agents in methods to increasethe efficiency of training protocols for enhancing a neurologicalfunction or treating a neurological impairment associated with aneurological disorder. Such methods are known as “augmented training,”and more particularly, in the case of cognitive impairments, “augmentedcognitive training,” and in the case of motor impairments, “augmentedmotor training.” Augmenting agents can act by shortening the time thatmethods of rehabilitating (or enhancing) a cognitive or motor functionresult in improved performance or a functional gain. Such augmentedtraining therefore comprises a specific training protocol for aparticular brain function, such as that underlying declarative memory,performance of a fine motor skill, a specific locomotor function,language acquisition, executive function, etc.; and a generaladministration of an augmenting agent of the present disclosure.

Training (or a “training protocol”) generally requires many sessions toattain the desired benefits, for example, to rehabilitate a motordeficit or language deficit following stroke. This can be costly andtime-consuming, deterring subject compliance and the realization of realworld benefits that endure over time. The efficiency of such trainingprotocols can be improved by administering certain agents (known asaugmenting agents) in conjunction with the training protocol (See, e.g.,U.S. 7,868,015; U.S. 7,947,731; U.S. 2008-0188525). When administered incombination with training protocols (or “training”), augmenting agentsenhance functional reorganization in targeted domains (or “functions”)in the brain.

Cognitive domains (or “functions”) that can be targeted by trainingprotocols include, but are not limited to, the following: attention(e.g., sustained attention, divided attention, selective attention,processing speed); executive function (e.g., planning, decision, andworking memory); learning and memory (e.g., immediate memory; recentmemory, including free recall, cued recall, and recognition memory; andlong-term memory, which can be divided into explicit memory (e.g.,declarative memory) memory, such as episodic, semantic, andautobiographical memory, and into implicit memory (e.g., proceduralmemory)); language (e.g., expressive language, including naming, wordrecall, fluency, grammar, and syntax; and receptive language);perceptual-motor functions (e.g., abilities encompassed under visualperception, visuo-constructional, perceptual-motor praxis, and gnosis);and social cognition (e.g., recognition of emotions, theory of mind). Inspecific embodiments, the cognitive function is learning and memory, andmore particularly, long term memory.

Motor domains (or functions) that can be targeted by training protocolsinclude, but are not limited to, those involved in gross body control,coordination, posture, and balance; bilateral coordination; upper andlower limb coordination; muscle strength and agility; locomotion andmovement; motor planning and integration; manual coordination anddexterity; gross and fine motor skills; and eye-hand coordination.

Training Protocols

Training protocols (or “modules”) include cognitive training and motortraining protocols. Training protocols are well-known in the art andtypically comprise a set of distinct exercises that can beprocess-specific or skill-based. See, e.g., Kim et al., 2014, J. Phys.Ther. Sci. 26, 1-6; Allen et al., 2012, Parkinson’s Dis. 1-15; Jaeggi etal., 2011, Proc. Natl. Acad. Sci. USA 108, 10081-10086; Chein et al.,2010, Psychon. Bull. Rev. 17, 193-199; Klingberg, 2010, Trends Cogn.Sci. 14, 317-324; Owen et al., 2010, Nature 465, 775-778; Tsao et al.,2010, J. Pain 11, 1120-1128; Lustig et al., 2009, Neuropsychol. Rev. 19,504-522; Park and Reuter-Lorenz, 2009, Ann. Rev. Psych. 60, 173-196;Oujamaa et al., 2009, Ann. Phys. Rehabil. Med. 52, 269-293; Frazzitta etal., 2009, Mov. Disord. 8, 1139-1143; Jaeggi et al., 2008, Proc. Natl.Acad. Sci. USA 105, 6829-6833; Volpe et al., 2008, Neurorehabil. NeuralRepair 22, 305-310; Fischer et al., 2007, Top. Stroke Rehab. 14, 1-12;Jonsdottir et al., 2007, Neurorehabil. Neural Repair 21, 191-194;Stewart et al., 2006, J. Neurol. Sci. 244, 89-95; Krakauer, 2006, Curr.Opin. Neurol. 19, 84-90; Belleville et al., 2006, Dement. Geriatr. Cogn.Disord. 22, 486-499; Klingberg et al., 2005, J. Am. Acad. Child.Adolesc. Psychiatry 44, 177-186; Dean et al., 2000, Arch. Phys. Med.Rehabil. 81, 409-417; Whitall et al., 2000, Stroke 31, 2390-2395;Hummelsheim and Eickhof, 1999, Scand. J. Rehabil. Med. 31, 250-256;Merzenich et al., 1996, Science 271, 77-81; Merzenich et al., 1996, ColdSpring Harb. Symp. Quant. Biol. 61, 1-8; Rider and Abdulahad, 1991,Percept. Mot. Skills 73, 219-224.

Process-specific training focuses on improving a particular domain suchas attention, memory, language, executive function, or motor function.Here the goal of training is to obtain a general improvement thattransfers from the trained activities to untrained activities based onthe same cognitive or motor function or domain.

Skill-based training is aimed at improving performance of a particularactivity or ability, such as learning a new language, performing amusical instrument, improving memory, or learning a fine motor skill.The different exercises within such a protocol will focus on corecomponents within one or more domains underlying the skill. Modules forincreasing memory, for example, may include tasks directed to specificdomains involved in memory processing, e.g., the recognition and use offacts, and the acquisition and comprehension of explicit knowledgerules.

In some embodiments, the battery of exercises is administered as part ofa single training session. In one aspect, the training protocolcomprises multiple training sessions, each separated by a discreteinterval. In another aspect, the number of training sessions sufficientto improve performance is reduced compared to that produced by trainingalone.

In a further aspect, the augmenting agent is a PDE1 inhibitor, and moreparticularly, is a chemical entity of the present disclosure, and isadministered in conjunction with training. The phrase “in conjunctionwith” means that the augmenting agent enhances CREB pathway functionduring training. In some embodiments, the deficit is a motor deficit. Inother embodiments, the deficit is a cognitive deficit. In still otherembodiments, the deficit may include both a cognitive and motor deficit.In other aspects, the compound is administered before and during eachtraining session. In one aspect, the subject is a human. In someembodiments, the subject is a non-human, and more particularly, is aprimate or a canine.

In one aspect, a chemical entity or composition of the presentdisclosure can be used as an augmenting agent in conjunction with anypsychotherapeutic approach intended to modulate cognitive function inthe brain, thereby enhancing the efficacy of such therapy by reducingthe amount of training, e.g., the number of sessions, necessary toattain benefits. In a specific aspect, the chemical entity is a compoundof Formula (I), or pharmaceutically acceptable salt thereof. Moreparticularly, the chemical entity is a compound of Formula (Ia), (Ib),(Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc), or apharmaceutically acceptable salt thereof.

Accordingly, in some embodiments, the disclosure provides the use of achemical entity or composition herein in a method of augmented trainingto treat a neurological disorder, the method comprising: (a) providingtraining to an animal in need of treatment of a neurological impairmentassociated with the neurological disorder under conditions sufficient toproduce an improvement in performance by said animal of a neurologicalfunction whose deficit is associated with said neurological impairment;(b) administering the chemical entity or composition to the animal inconjunction with said training; (c) repeating said providing andadministering steps one or more times; and (d) reducing the amount oftraining sufficient to produce the improvement in performance, relativeto the improvement in performance produced by training alone. Inspecific embodiments, the animal is a human subject. In some aspects,the augmented training is augmented cognitive training. In some aspects,the neurological impairment is a cognitive impairment. In some aspects,the neurological impairment is a motor impairment. In a specific aspect,the neurological disorder is stroke or traumatic brain injury. In someaspects, the augmented training is provided to a stroke patient duringpost-stroke rehabilitation, as described further herein. In a specificaspect, the chemical entity is a compound of Formula (I), orpharmaceutically acceptable salt thereof. In some embodiments, trainingcomprises spaced training sessions. In other embodiments, trainingcomprises massed training sessions.

Animal Skill Protocols

In some embodiments, chemical entities of the present invention are usedto enhance the efficiency of training protocols directed to cognitiveand motor skills in an animal. Such augmented training (augmenting agentand training) reduces the time necessary to acquire a cognitive or motorskill, and/or enhance function or cognitive ability beyond what would bepossible by training alone in the non-human animal.

In particular embodiments, the animal is a non-human animal, and moreparticularly, is a service animal, a category that includes, but is notlimited to, dogs, miniature horses, and capuchin monkeys. Serviceanimals may be involved in public service or private service, and thetraining protocols will be appropriately matched to these objections.For example, training protocols directed to public service includepublic order maintenance, search and rescue, and contraband detection,and training protocols directed to private service include privatesecurity, handicap assistance, health care, psychiatric assistance, andpest control.

The training protocol may be directed to a single skill, such as thedetection of a specific contraband category by a service animal. Inother embodiments, the training protocol may be directed to a complexset of skills, such as those underlying search and rescue training of aservice animal; for a complex set of skills, training will thereforecomprise more than one tasks.

Accordingly, in some embodiments, the present invention provides amethod of teaching a non-human animal one or more skills, comprising (a)administering to a non-human animal in need thereof a PDE1 inhibitor;(b) providing training to the animal under conditions sufficient toimprove performance of the one or more skills; and (c) repeating steps(a) and (b) one or more times, whereby the amount of training sufficientto improve the performance is reduced compared to that produced bytraining alone.

Stroke

In certain embodiments, chemical entities and compositions of thepresent disclosure are useful in methods of treating a trauma-dependentloss of function, and more particularly, stroke. Stroke is a leadingcause of serious long-term disability in adults and is the secondleading cause of death worldwide (e.g., Go et al., 2014, Circulation129, e28-e92). Stroke is comprises two main types: 1) ischemic strokewhich occurs when blood vessels supplying the brain are blocked by clotformation (85% of all strokes) and 2) hemorrhagic stroke which occurswhen blood vessels rupture within the brain (13 - 15% of all strokes).Stroke care is a temporal continuum that includes medical interventionduring the acute phase of stroke and subsequent rehabilitative therapydirected to restoring function during the post-stroke phase of stroke.

Acute Treatments

Treatments following the onset of stroke directly target the initialdamage triggered by ischemic or hemorrhagic stroke. Acute treatmentoptions for ischemic stroke include pharmacotherapy with intravenousrecombinant tissue plasminogen activator (r-tPA) to thrombolyze theclot, or the use of endovascular procedures or mechanical thrombectomyto physically remove the clot. Acute treatment options for hemorrhagicstroke typically involve endovascular or surgical procedures tophysically repair the rupture.

Post-Stroke Rehabilitation

Following the acute phase of stroke— and typically after the patient hasbeen medically stabilized — the focus of stroke treatment shifts torestoring function by rehabilitation. Depending on the severity andlocation of the stroke as well as the timing and effectiveness of acuteinterventions, post-stroke symptoms may persist and can include motordeficits (e.g., hemiparesis, apraxia), speech impairment (e.g.,aphasia), visual impairments (e.g., visual field loss), emotional andbehavioral changes (e.g., depression, anxiety), and mental and cognitivechanges (e.g., confusion, apathy, cognitive impairment) (Winstein etal., 2016, Stroke 47, e98-e169). Rehabilitation (also referred to as“stroke rehabilitation” or “post-stroke rehabilitation”) is directed topost-stroke deficits, such as cognitive and motor deficits that persistafter the initial stroke injury. The goal is to restore and recoverneurological functions, e.g., physical, intellectual, psychological, andsocial functions, as much as possible to compensate for the permanenttissue loss (e.g., 1995 Clinical Guideline by the Department of Healthand Human Services on Post-Stroke Rehabilitation).

Stroke rehabilitation is typically a comprehensive program coordinatedby a team of medical professionals, which may include occupational,speech, and physical therapists. A physical therapist on the team, forexample, may focus on maintaining and restoring range of motion andstrength in affected limbs, maximizing mobility in walking, improvingmanual dexterity, and rehabilitating other motor and sensorimotorfunctions. A mental health professional may be involved in the treatmentof loss of cognitive skills. Rehabilitation services can occur inmultiple environments, such as a rehabilitation hospital, long-term carefacility, outpatient clinic, or at home.

Neurological functions impacted by stroke (and which can be targetedduring rehabilitation) include impairments in cognitive and motorfunctions. Cognitive function impairments, for example, can manifest asdeficits in understanding speech or writing (aphasia); knowing the rightwords but having trouble saying them clearly (dysarthria); as well asdeficits in other cognitive functions, such as attention, reasoning,planning, execution, and learning and memory. Motor functionimpairments, for example, can manifest as weakness (hemiparesis) orparalysis (hemiplegia) on one side of the body that may affect the wholeside or just the arm or leg; as problems with balance or coordination;as deficits in gross motor skills such as gait and walking speed; asdeficits in fine motor skills or manual dexterity; and as deficits inupper and lower extremity function.

In the United States, more than 700,000 people suffer a stroke eachyear, two-thirds of these survive and require rehabilitation.Unfortunately, recovery is generally only partial and considerabledeficits persist in many patients (e.g., Gordon et al., 2004, Stroke 35,1230-1240). For example, after standard rehabilitation, approximately30% to 60% of patients are left without functional use of theirparetic/plegic arm (Gowland, 1982, Physiother. Can.34, 77-84; Kwakkel etal., 1996, Age Ageing 25, 479-489), and despite intensive rehabilitationefforts, only approximately 5% to 20% reach complete functional recoveryof their arm (Nakayama et al., 1994, Arch. Phys. Med. Rehabil.75,394-398).

As discussed herein, chemical entities, and compositions thereof, of thepresent disclosure are used as augmenting agents to increase theefficiency of training protocols for treating a neurological impairment,which encompasses impairments due to traumatic events such as stroke.Accordingly, in some embodiments, the present disclosure providesmethods of treating a neurological deficit during post-strokerehabilitation comprising: (a) administering to a subject in needthereof a PDE1 inhibitor disclosed herein during recovery of the subjectfrom stroke; (b) providing training to the subject under conditionssufficient to improve performance of a neurological function whoseimpairment is due to the deficit; and (c) repeating steps (a) and (b)one or more times, whereby the amount of training sufficient to improvethe performance is reduced compared to that produced by training alone.

In some embodiments, administration can begin during the acute stage. Inother embodiments, the PDE1 inhibitor is administered only after theacute stage, i.e., during post-stroke rehabilitation, which may includesub-acute and chronic stages. In some embodiments, administration occursduring the acute stage and post-stroke stage. In some embodiments, thePDE1 inhibitor is administered chronically, meaning that it is indicatedfor long-term use after the acute stage of the stroke has ended and thepatient has been medically stabilized.

In other embodiments, the subject is a post-stroke patient, and PDE1inhibitors are administered during stroke rehabilitation to treat strokedeficits (or “post-stroke deficits”) resulting from impairedneurological functions. In some embodiments, the deficit is a motordeficit, including upper or lower extremity motor deficit. In otherembodiments, the deficit is a cognitive deficit, such as such asaphasia, apraxia, and mental and cognitive changes, particularly, adeficit in memory formation, and more specifically, a deficit inlong-term memory formation. In still other embodiments, the deficit mayinclude a cognitive and motor deficit. In another aspect, trainingcomprises a battery of tasks directed to the neurological function. In aspecific aspect, the reduction in the amount of training is a reductionin the number of training sessions.

In a further embodiment, the administering step (a) is in conjunctionwith the training step (b). In one aspect, the subject is a human. Inanother aspect, the subject has undergone neuronal stem cellmanipulation. In other aspects, the compound is administered before andduring each training session.

Traumatic Brain Injury

In some embodiments, chemical entities and compositions are useful inmethods of treating traumatic brain injury (TBI), and in more specificembodiments, treating motor or cognitive impairments duringrehabilitation of TBI after the initial trauma.

TBI, also known as intracranial injury, occurs when an external forceinjures the brain. TBI can be classified based on severity, mechanism(closed or penetrating head injury), or other features (e.g., occurringin a specific location or over a widespread area). TBI can result inphysical, cognitive, social, emotional, and behavioral symptoms. Causesinclude falls, vehicle collisions, gunshot injuries, and explosives.Outcomes can range from complete recovery to permanent disability ordeath.

Like stroke care, TBI case is a temporal continuum that includes acute(or sub-acute) treatments directed to the injury itself and subsequentrehabilitative therapy directed to restoring function.

Accordingly, in some embodiments, the chemical entities and compositionsof the present disclosure are useful during the acute (or sub-acute)stage of TBI, during which their administration can treatneuroinflammatory and neurodegenerative events following the primaryinjury.

Some embodiments provide the use of a PDE1 inhibitor disclosed duringTBI rehabilitation to treat TBI deficits (or “post-TBI deficits”)resulting from impaired neurological functions. Some embodiments providemethods of treating a neurological deficit during post-TBIrehabilitation comprising: (a) administering to a subject in needthereof a PDE1 inhibitor during recovery of the subject from TBI; (b)providing training to the subject under conditions sufficient to improveperformance of a neurological function whose impairment is due to thedeficit; and (c) repeating steps (a) and (b) one or more times, wherebythe amount of training sufficient to improve the performance is reducedcompared to that produced by training alone.

In one aspect, the PDE1 inhibitor is a chemical entity of the presentdisclosure, and more specifically, is a compound, or pharmaceuticallyacceptable salt thereof, of Formula (I). More particularly, the chemicalentity is a compound of Formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa),(Icab), (Icb), or (Icc), or a pharmaceutically acceptable salt thereof.In some embodiments, the deficit is a motor deficit. In otherembodiments, the deficit is a cognitive deficit, particularly, a deficitin memory formation, and more specifically, a deficit in long-termmemory formation. In still other embodiments, the deficit may include acognitive and motor deficit. In another aspect, training comprises abattery of tasks directed to the neurological function. In a specificaspect, the reduction in the amount of training is a reduction in thenumber of training sessions.

In a further embodiment, the administering step (a) is in conjunctionwith the training step (b). In one aspect, the subject is a human. Inanother aspect, the subject has undergone neuronal stem cellmanipulation. In other aspects, the compound is administered before andduring each training session.

Peripheral Disorders

In some embodiments, the present disclosure provides methods of treatinga peripheral disorder (i.e., a disorder other than a primaryneurological disorder), comprising administering to a subject in needthereof an effective amount of a chemical entity or compositiondisclosed herein. In one embodiment of these methods, the chemicalentity is a compound, or pharmaceutically acceptable salt thereof, ofFormula (I). More particularly, the chemical entity is a compound ofFormula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc),or a pharmaceutically acceptable salt thereof.

Peripheral disorders involving PDE1 include a wide variety of diseases,based on numerous biological studies and the expression of PDE1subtypesin peripheral tissues, such as the heart, lungs, veins and arteries,smooth muscle, skeletal muscle, skin, adrenal gland, thyroid, pancreas,esophagus, stomach, small intestine, colon, liver, leukocytes, testis,ovary, bladder, and kidney. See, e.g., Bender and Beavo, 2006,Pharmacol. Rev.58, 488-520. Accordingly, peripheral disorders that canbe treated by compounds and compositions of the present inventioninclude, but are not limited to, cardiovascular disorders, renaldisorders, hematological disorders, gastrointestinal and liverdisorders, cancer disorders, fertility disorders, and metabolic diseasessuch as diabetes and obesity.

Peripheral disorders also include, in certain embodiments, diseases andconditions (other than primary neurological disorders) characterized bylow levels of cAMP or cGMP in cells expressed PDE1, by inhibition ofcAMP or cGMP signaling pathways in cells expressing PDE1, and by reduceddopamine D1 receptor signaling activity.

Cardiovascular Disorders

In certain embodiments, the peripheral disorder is a cardiovasculardisorder. PDE1 enzymes and cyclic nucleotides are emerging as keymediators of pathological processes that underlie many vasculardisorders, including hypertension and myocardial infarction. All threePDE1 isoforms are expressed in the human pulmonary artery, as well asthe aorta and small mesenteric arteries (Schermuly et al., 2007,Circulation 115, 2331-2339; Murray et al., 2007, Am. J. Physiol. LungCell. Mol. Physiol., 292, L294-L303). In addition, selective PDE1inhibition induces vasodilation and lower blood pressure in rats(Laursen et al., 2017, Br. J. Pharmacol.174, 2563-2575). Moreover, PDE1enzymes constitute the majority of cAMP- and cGMP-hydrolytic activity inhuman myocardium, implicating them in the modulation of signalingpathways involved in heart failure.

Accordingly, the present invention includes the use of a compound orcomposition herein in a method of treating a cardiovascular disorder,comprising administration of an effective amount of a chemical entity orcomposition to a patient in need thereof.

Cardiovascular diseases within the scope of the present inventionencompass, but are not limited to, angina pectoris, coronary arterydisease, hypertension, congestive heart failure, myocardial infarction,ischemic diseases of the heart, atrial and ventricular arrhythmias,hypertensive vascular diseases, peripheral vascular diseases, pulmonaryhypertension (PH) (or pulmonary arterial hypertension (PAH)),atherosclerosis, and other pulmonary and respiratory disorders.

In some embodiments, methods of treating a cardiovascular disorder inaccord with the present invention comprise increasing cGMPconcentration, cAMP concentration, or both, in any part of the heartmuscle of a subject, the method comprising administering to the subjecta chemical entity or composition described herein.

In other embodiments, chemical entities and compositions of the presentinvention may be useful in lowering the heart rate or blood pressure inan animal.

Renal Disorders

In certain embodiments, the peripheral disorder is a renal disease. PDE1inhibitors are emerging therapeutic agents for progressive renaldisease. See, e.g., Cheng et al., 2007, Soc. Exp. Biol. Med.232, 38-51.Consistent with these findings, recent studies indicate that cAMP andcGMP regulate a variety of signaling pathways involved in thedevelopment and progression of renal disease, including pathways thatmodulate mitogenesis, inflammation, and extracellular matrix synthesis.See, e.g., Wang et al., 2010, Kidney Int. 77. 129-140; Wang et al.,2017, PLoS One 12, e0181087.

Accordingly, the present invention provides chemical entities orcompositions in methods for treating a renal disorder, comprisingadministering an effective amount of the chemical entity or compositionto a patient in need thereof. In a particular aspect, the renal disorderis selected from one or more of the group comprising renal arterystenosis, pyelonephritis, glomerulonephritis, kidney tumors, polycystickidney disease, injury to the kidney, and damage resulting fromradiation of the kidney, and autosomal dominant polycystic kidneydisease (ADPKD).

Hematological Disorders

In certain embodiments, the peripheral disorder is a hematologicaldisorder. PDE1B is highly expressed in the hematological system,including leukocytes (peripheral blood), bone marrow stromal cells, bonemarrow CD33+ cells, cord blood CD34+ cells, neutrophils cord blood,neutrophils peripheral blood, spleen, spleen liver cirrhosis.Accordingly, the present invention includes methods to treat ahematological disorder, comprising administering a chemical entity orcomposition herein to a patient in need thereof. Hematological diseaseswithin the scope of the present invention comprises disorders of theblood and all its constituents, including, but not limited to anemias,myeloproliferative disorders, hemorrhagic disorders, leukopenia,eosinophilic disorders, leukemias, lymphomas, plasma cell dyscrasias,and disorders of the spleen.

Gastrointestinal and Liver Diseases

In certain embodiments, the peripheral disorder is a gastrointestinal orliver disease. PDE1B shows differential expression between diseased(e.g., cancerous) and healthy stomach tissue, diseased (e.g., cancerous)versus healthy ileum tissue, diseased (cirrhotic) versus and healthyliver. Accordingly, the present invention includes methods to treat agastrointestinal or liver disorder, comprising administering a compoundor composition herein to a patient in need thereof. Gastrointestinal andliver diseases within the scope of the present invention comprise, butare not limited to, disorders of the esophagus, stomach, duodenum,pancreas, bowel, and liver.

Cancer Disorders

In certain embodiments, the peripheral disorder is a cancer disorder.PDE1B shows high expression in numerous cancer tissues, including tumorsof the stomach, ileum, ovary, breast, and kidney, as well asdifferential expression between cancerous and healthy stomach, ileum,lung, ovary, breast, and kidney. Accordingly, the present inventionincludes methods to treat a cancer disorder, comprising administering acompound or composition herein to a patient in need thereof. Cancerdisorders within the scope of the present invention comprise, but arenot limited to, neoplasms, dysplasias, hyperplasias, and neoplasms,including cancers of the stomach, ileum, ovary, breast, and kidney.

Fertility Disorders

In certain embodiments, the peripheral disorder is a fertility disorder.PDE1 inhibitors, for example, have been implicated in the enhancement ofprogesterone signaling (e.g., WO 2008/070095). Accordingly, the presentinvention includes methods to treat a fertility disorder, comprisingadministering a compound or composition herein to a patient in needthereof. Fertility disorders within the scope of the present inventioncomprise female sexual dysfunction and disorders involving impairmentsin progesterone signaling, which include, but are not limited to,exercise amenorrhea, anovulation, menopause, menopausal symptoms,hypothyroidism, pre-menstrual syndrome, premature labor, infertility,irregular menstrual cycles, abnormal uterine bleeding, osteoporosis,autoimmune disease, multiple sclerosis, estrogen-induced endometrialhyperplasia and estrogen-induced endometrial carcinoma.

Treatment Combinations

Chemical entities and compositions of the present disclosure can beadministered as a monotherapy or as part of a combination therapy.“Monotherapy” refers to a treatment regimen based on the delivery of one(e.g., one and only one) therapeutically effective chemical entity orcomposition thereof.

In a combination therapy, one or more chemical entities or compositionsof the present invention can be co-administered or used in combinationwith one or more additional agents (or therapies), such as additionalagents (or therapies) known in the art. Such administration may besimultaneous, sequential, or staggered. In certain embodiments, theadditional agent (or therapies) is based on a different target ormodality (e.g., is not a PDE1 inhibitor).

In some embodiments, the combination is administered as part of anadjunct (or adjunctive) therapy, in which one agent is given in additionto a primary agent to assist or maximize the effectiveness of theprimary agent.

In specific embodiments, the combination is administered to treatschizophrenia, Parkinson’s disease, Alzheimer’s disease, Huntington’sdisease, anxiety and depressive disorders, or stroke. In someembodiments, a chemical entity or composition disclosed herein isadministered as an adjunct therapy in conjunction with a dopamineprecursor, such as levodopa, to treat Parkinson’s disease or a relateddisorder.

Exemplary agents for treating schizophrenia include, but are not limitedto, clozapine, aripiprazole, brexpiprazole, cariprazine, lurasidone,paliperidone, quetiapine, risperidone, olanzapine, ziprasidone, andiloperidone.

Exemplary agents for treating Parkinson’s disease include, but are notlimited to, dopamine preparations (including dopamine precursors such aslevodopa), dopamine agonists, or COMT agents (drugs that inhibit theaction of catechol-methyl transferase).

Exemplary agents for treating Alzheimer’s disease include, but are notlimited to, donepezil, rivastigmine, galantamine, marijuana-likecannabinoids, and memantine.

Exemplary agents for treating Huntington’s disease (or other motordisorders) may include, but are not limited to, tetrabenazine, as wellas antipsychotic drugs such as haloperidol, chlorpromazine, risperidone,and quetiapine, and anti-epileptic drugs such as levetiracetam andclonazepam, which may be beneficial in treating chorea or related motordisorders.

Exemplary agents for treating anxiety or depression include, but are notlimited to, benzodiazepines and other anxiolytics; serotonin reuptakeinhibitors (SSRIs), such as sertraline, fluoxetine, citalopram,escitalopram, paroxetine, fluvoxamine, and trazodone; serotonin andnorepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine,duloxetine, levomilnacipran, and venlafaxine; tricyclic antidepressants(TCAs), such as amitriptyline, amoxapine, clomipramine, desipramine,doxepin, imipramine, nortriptyline, protriptyline, and trimipramine;monoamine oxidase inhibitors (MAOIs), such as isocarboxazid, phenelzine,selegiline, and tranylcypromine; and other classes of drugs, such asmaprotiline, bupropion, vilazodone, nefazodone, trazodone, vortioxetine,and mirtazapine

Exemplary agents for treating stroke include, but are not limited to, athrombolytic agent (e.g., streptokinase, acylatedplasminogen-streptokinase activator complex (APSAC), urokinase,single-chain urokinase-plasminogen activator (scu-PA), anti-inflammatoryagents, thrombin-like enzymes, tissue plasminogen activator (t-PA); ananticoagulant (e.g., warfarin or heparin); an antiplatelet drug (e.g.,aspirin); a glycoprotein IIb/IIIa inhibitor; a glycosaminoglycan;coumarin; GCSF; melatonin; an apoptosis inhibitor (e.g., caspaseinhibitor), an anti-oxidant (e.g., NXY-059); and a neuroprotectant(e.g., an NMDA receptor antagonists or a cannabinoid antagonist).

The preceding list of additional active agents is meant to be exemplaryrather than fully inclusive. Additional active agents not included inthe above list may be administered in combination with a compound ofFormula (I) such as those know for treating peripheral disordersdescribed herein. The additional active agent will be dosed according toits approved prescribing information, though in some embodiments theadditional active agent may be dosed at less the typically prescribeddose.

EXAMPLES

The present disclosure will be further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of the oneor more embodiments, and as defined by the appended claims.

Preparative Examples

Exemplary compounds will now be described by reference to theillustrative synthetic schemes for their general preparation below andthe specific examples to follow.

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between -100° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

TABLE 1 Abbreviation Definition ACN Acetonitrile Ac₂O Acetic anhydrideBoc tert-Butyloxycarbonyl Boc₂O Di-tert-butyl dicarbonate CAS Chemicalabstracts service CCl₄ Carbon tetrachloride CDCl₃ Deuterated chloroformCelite® Diatomaceous earth CHCl₃ Chloroform CH₂=CHBF₃K Potassiumvinyltrifluoroborate CsF Cesium fluoride Cs₂CO₃ Cesium carbonate DCM,CH₂Cl₂ Dichloromethane DCE Dichloroethane DIPEA, DIEAN,N-ethyldiisopropylamine or N,N-Diisopropylethyl amine DMAN,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethylsulfoxidedppf 1,1′-Bis(diphenylphosphino)ferrocene EtOAc, or EA Ethyl acetateEtOH Ethanol FCC Flash column chromatography H₂ Hydrogen HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HCl Hydrochloric acid HCO₂H Formic acid H₂OWater HPLC High-performance liquid chromatography IPA Isopropyl alcoholK₂CO₃ Potassium carbonate KF Potassium fluoride MeOH Methanol 2-MeTHF2-Methyltetrahydrofuran MgSO₄ Magnesium sulfate N₂ Nitrogen NaCl Sodiumchloride, brine Na₂CO₃ Sodium carbonate NaOMe Sodium methoxide NaOEtSodium ethoxide Na₂SO₃ Sodium sulfite Na₂SO₄ Sodium sulfate NISN-Iodosuccinimide Pd Palladium Pd/C Palladium on carbon, 10% Pd(dppf)Cl₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl₂·CH₂Cl₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)PPh₃ Triphenylphosphine POCl₃ Phosphorous oxychloride, phosphorouschloride RT, rt Room temperature SFC Supercritical fluid chromatographySiO₂ Silica gel TEA, Et₃N Triethylamine TFA Trifluoroacetic acid THFTetrahydrofuran ZnCN₂ Zinc cyanide, dicyanozinc

Synthetic Schemes

According to Scheme A,6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) can be synthesized from ethyl2-chloro-3-oxobutanoate in 5 steps from commercially available startingmaterials. Treatment of ethyl 2-chloro-3-oxobutanoate with malonitrile,in a solvent such as ethanol, or the like, followed by a base such assodium ethoxide, or the like, at a temperature ranging from -78° C. tort, sometimes a temperature ranging from -10° C. to 10° C., providesethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate. Treatment of ethyl5-amino-4-cyano-2-methylfuran-3-carboxylate with formic acid, followedby acetic anhydride, at a temperature ranging from rt to 100° C., for atime period of up to 48 hours, provides ethyl4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Subsequentchlorination, using conditions known to one of skill in the art, forinstance treatment with phosphorous oxychloride, in the presence of abase such as N,N-diisopropylethylamine, or the like, with or without asolvent, at a temperature ranging from rt to 100° C., sometimes 85° C.,provides ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Anucleophilic aromatic substitution reaction, using1-methylcyclopropanamine hydrochloride as the amine, followed byhydrolysis of the ester, under conditions known to one of skill in theart, provides6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1). For example, treatment of the arylchloride with1-methylcyclopropylamine hydrochloride, in a solvent such asisopropanol, or the like, in the presence of a base such astriethylamine, at a temperature ranging from rt to 80° C., sometimes 45°C., provides ethyl6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate.Subsequent base-catalyzed ester hydrolysis, using a base such as lithiumhydroxide, or the like, in a solvent mixture such as tetrahydrofuran andmethanol, or the like, at room temperature for several hours, provides6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1).

In a similar fashion, base-catalyzed hydrolysis of ethyl4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate, under conditionsknown to one of skill in the art, such as those described above,provides 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic acid(Intermediate 2).

According to Scheme B, compounds of formula (VII) and (VIII) can besynthesized from the corresponding boronic acid pinacol ester startingmaterial.

A compound of formula (IVa), where R¹ is C₁₋₆alkyl, C₁₋₆haloalyl,C₃₋₇cycloalkyl, can be synthesized by a nucleophilic aromaticsubstitution reaction of an amine and an aryl chloride of formula (III),where R² is an optionally substituted aryl or heteroaryl group and X isCl, Br, or I. A subsequent Suzuki coupling of a boronic acid pinacolester of formula (II) and a commercially available or syntheticallyaccessible aryl halide or heteroaryl halide of formula (IVa) or (IVb),under conditions known to one of skill in the art, provides a compoundof formula (V), where R³ is an optionally substituted aryl or heteroarylgroup (with the optional substitution including -NHR¹). For example,treatment of (II) with tetrakis(triphenylphosphine)palladium(0), in thepresence of a base such as potassium carbonate or the like, in a solventmixture such as ethanol and dioxane, or the like, at a temperatureranging from 80° C. to 150° C., provides a compound of formula (V),where α is 1 or 2 and R³ is an optionally substituted aryl or heteroarylgroup. Subsequent reduction of the double bond in a catalytichydrogenation, using conditions known to one of skill in the art,followed by removal of the tert-butoxycarbonyl protecting group underacidic conditions, provides a compound of formula (VII). For example,using a catalyst such as palladium on carbon, or the like, under anatmosphere of hydrogen, provides a compound of formula (VI). Subsequenttreatment with a strong acid such as trifluoroacetic acid in a solventsuch as dichloromethane, or the like, or hydrochloric acid in a solventsuch as dioxane, or the like, provides an amine of formula (VII), whereα is 1 or 2 and R³ is an optionally substituted aryl or heteroarylgroup. Alternatively, treatment of a compound of formula (V) with astrong acid, under conditions known to one of skill in the art, asdescribed above, provides a dihydropyrrole or tetrahydropyridinecompound of formula (VIII), where α is 1 or 2 and R³ is an optionallysubstituted aryl or heteroaryl group.

According to Scheme C, an aryl chloride can be converted to an arylfluoride using conditions known to one of skill in the art. Forinstance, treatment of a compound of formula (IX) with cesium fluoride,in a solvent such as DMSO, or the like, at a temperature ranging from40° C. to 100° C., sometimes 70° C., provides an aryl fluoride offormula (X). Subsequent removal of the t-butoxycarbonyl protectinggroup, as previously described, provides an amine of compound (XI),where b is 0 or 1, c is 1 or 2, and B, D, E and G are C or N.

Synthesis of an aryl amine of formula (XIII) from an aryl chloride offormula (IX) is achieved by a nucleophilic aromatic substitution, underconditions known to one of skill in the art, followed by removal of thetert-butoxycarbonyl protecting group. For example, treatment of the arylchloride with an amine, in the presence of a base such asN,N-diisopropylethylamine, or the like, in a solvent such as DMA or DMF,or the like, heated to a temperature ranging from 40° C. to 160° C.,sometimes 80° C., provides a compound for formula (XII). Subsequentdeprotection of the amine using conditions known to one of skill in theart, as previously described, provides an amino compound of formula(XIII), where b is 0 or 1; c is 1 or 2; B, D, E and G are C or N; and R⁴and R⁵ are independently H or an optionally substituted C₁₋₆alkyl or C₃₇cycloalkyl group, or R⁴ and R⁵ come together to form an optionallysubstituted heterocycloalkyl group.

Treatment of a compound of formula (IX) with a strong acid, such as HClor TFA, under conditions previously described, provides an aminecompound of formula (XIV), where b is 0 or 1, c is 1 or 2, and B, D, Eand G are C or N.

A nucleophilic substitution reaction of a compound of formula (XV),where X is Cl, Br or I, with an amine provides a compound of formula(XVI). For example, treatment of the alkyl halide with an amine, in thepresence of a base such as potassium carbonate, or the like, in asolvent such as ACN, DMF, or DMA, or the like, at a temperature rangingfrom rt to 100° C., sometimes 40° C., for many hours, provides acompound of formula (XVI), where d is 0 or 1; B, D, E and G are C or N;R⁶ is -halo, —OH, —CN or an optionally substituted amino, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl, aryl or heteroaryl group; and R⁷ is anoptionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group.

3-Cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-α]pyrazine can besynthesized from commercially available or synthetically accessible3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-α]pyrazine in 5 steps, asshown in Scheme E. Treatment of3-cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-α]pyrazine withdi-tert-butyl dicarbonate, in the presence of a base such asN,N-diisopropylethylamine or the like, in a solvent such as DCE, or thelike, at room temperature, provides tert-butyl3-cyclopropyl-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylate.Iodination of the imidazole, using conditions known to one of skill inthe art, such as treatment with NIS, or the like, in a solvent such asACN, or the like, provides tert-butyl3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylate.A subsequent Suzuki coupling of the aryl iodide with potassiumvinyltrifluoroborate, using palladium(0) as the catalyst, in thepresence of a base such as potassium carbonate or sodium carbonate, orthe like, in a solvent mixture such as ACN and water, or the like,heated to a temperature ranging from 60° C. to 110° C., sometimes 90°C., provides tert-butyl3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylate.Subsequent hydrogenation to reduce the alkene, followed by removal ofthe tert-butoxycarbonyl protecting group, provides the free aminecompound. For example, catalytic hydrogenation under conditions known toone of skill in the art, such as treatment of tert-butyl3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylatewith palladium on carbon, under an atmosphere of hydrogen, in a solventsuch as ethyl acetate, or the like, provides tert-butyl3-cyclopropyl-1-ethyl-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylate.Treatment of the tert-butoxycarbonyl protected compound withtrifluoroacetic acid, in a solvent such as 2-methyl tetrahydrofuran,provides 3-cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine.

A 4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compound of formula(XVIII) is synthetically accessible from commercially available1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate in two steps.Treatment of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylatewith a substituted amidine, in the presence of a base such as sodiumethoxide or the like, in a solvent such as ethanol, at a temperatureranging from 40° C. to 100° C., sometimes 90° C., provides atetrahydropyridopyrimidinone of formula (XVII), where R⁸ is H or anoptionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group.Chlorination using conditions known to one of skill in the art, forexample using carbon tetrachloride in the presence oftriphenylphosphine, in a solvent such as dichloroethane or the like, ata temperature of 70° C., provides a compound of formula (XVIII). Fromthis intermediate, several 4-substituted5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds are syntheticallyaccessible.

In one instance, a Suzuki coupling of an aryl chloride of formula(XVIII) with a boronic acid, boronic acid pinacol ester or potassiumtrifluoroborate salt of formula (XIX), where BL_(n) is B(OH)₂,B(O₂C₂(CH₃)₄), or BF₃K, under conditions known to one of skill in theart, provides a compound of formula (XX). For example, using conditionssimilar to the Suzuki coupling described in Scheme E, using[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride as thecatalyst and sodium carbonate as the base, provides a compound offormula (XX), where R⁸ is H or an optionally substituted C₁₋₆alkyl,C₁₋₆haloalkyl or C₃₋₇cycloalkyl group, and R¹⁰, R¹¹ and R¹² areindependently H or C₁₋₆alkyl, or R⁹ and R¹⁰ taken together can form anoptionally unsaturated C₄₋₆cycloalkyl or unsaturatedC₄₋₆heterocycloalkyl group. Removal of the tert-butoxycarbonylprotecting group provides a compound of formula (XXI). Alternatively,reduction of an alkene of a compound of formula (XX) in a catalytichydrogenation reaction, followed by deprotection of thetert-butoxycarbonyl protecting group, as described previously in SchemeB, provides a compound of formula (XXII), where R⁸ is H or an optionallysubstituted C₁₋₆alkyl or C₃₋₇cycloalkyl group, and R¹⁰, R¹¹ and R¹² areindependently H or C₁₋₆alkyl or R¹⁰ and R¹¹ taken together can form anoptionally substituted saturated C₃₋₆cycloalkyl or saturatedC₃₋₆heterocycloalkyl group. Alternatively, compounds of the formula(XXIV) can be prepared directly from (XVIII) using a Suzuki reactionwith cyclopropylboronic acid, under conditions known to one of skill inthe art.

In another instance, in a nucleophilic aromatic substitution reactionwith an alkoxide, such as sodium methoxide, in a solvent such as THF orthe like, at a temperature ranging from 50° C. to 90° C., sometimes 70°C., provides a compound of formula (XXV), where R⁸ is H or an optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group, and R⁹ isan optionally substituted

C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group. Subsequentdeprotection of the amine, as previously described, affords a compoundof formula (XXVI).

In a metal-catalyzed cyanation reaction, under conditions known to oneof skill in the art, by treatment of an aryl chloride of formula (XVIII)with dicyanozinc, in the presence of a transition metal catalyst such astetrakis(triphenylphosphine)palladium(0), or the like, in a solvent suchas DMF or DMA or the like, at a temperature of 90° C. for several hours,followed by removal of the tert-butoxycarbonyl group, as previouslydescribed, affords an amine of formula (XXVII), where R⁸ is H or anoptionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group.

Various amide analogs can be synthesized from Intermediate 1, as shownin Scheme G.

A compound of formula (XXX), where R³ is an optionally substituted arylor heteroaryl group, can be synthesized in 1 or 2 steps fromIntermediate 1, step-wise by an amide coupling with a compound offormula (XXVIII) followed by a Suzuki coupling, or in one step by anamide coupling with a bicyclic intermediate of formula (VIII). Forexample, an amide coupling of Intermediate 1 with an amine of formula(XXVIII), where a is 1 or 2, under conditions known to one of skill inthe art, using a coupling reagent such as HATU or the like, in thepresence of a base such as N,N-diisopropylethylamine, triethylamine, orthe like, in a solvent such as DMA or DMF, or the like, provides acompound of formula (XXIX), where a is 1 or 2. Subsequently, a Suzukicoupling of a pinacol boronate ester with an aryl halide or heteroarylhalide of formula X-R³, where X is Cl, Br or I and R³ is an optionallysubstituted aryl or heteroaryl group, under conditions previouslydescribed in Scheme B, provides a compound of formula (XXX).Alternatively, a compound of formula (XXX) can be synthesized directlyfrom Intermediate 1 in an amide coupling with a bicycle of formula(VIII), using conditions previously described.

Synthesis of a compound of formula (XXXI), where a is 1 or 2 and R³ isan optionally substituted aryl or heteroaryl group, is achieved byeither catalytic hydrogenation of an alkene of formula (XXX), underconditions previously described, or by an amide coupling of Intermediate1 and a compound of formula (VII).

An amide coupling of Intermediate 1 with a amine, similar to conditionspreviously described, using a coupling agent such as HATU, or2-chloro-1-methylpyridin-1-ium iodide or the like, in the presence of abase such as N,N-diisopropylethylamine, triethylamine, or the like, in asolvent such as DMF or DMA, for several hours at room temperature,provides a compound of formula (XXXII) where R¹³ and R¹⁴ areindependently H or an optionally substituted C₁₋ ₆alkyl, C₁₋₆haloalkyl,C₁₋₄alkylaryl, or C₁₋₄alkyl-heteroaryl group; or R¹³ and R¹⁴ cometogether to form an optionally substituted N-containing heterocycloalkylgroup or an optionally substituted N-containing heteroaryl group.

According to Scheme H, various amide analogs can be synthesized fromIntermediate 1.

Formation of a fluoroalkoxy compound of formula (XXXV) is achieved intwo steps from Intermediate 1. First an amide coupling of Intermediate 1and an amine of (XXXIII), under conditions previously described,provides a hydroxyl-substituted compound of formula (XXXIV). Subsequentalkylation of the hydroxyl group, in a nucleophilic substitutionreaction, using a fluoro alkyl methylbenzenesulfonate compound, in thepresence of a base such as cesium carbonate, or the like, and a solventsuch as DMF or DMA or the like, at a temperature ranging from 40° C. to130° C., sometimes 70° C., provides a compound of formula (XXXV), whereb is 0 or 1; c is 1 or 2; e is 1, 2 or 3; and B, D, E and G are C or N.

An aryl fluoride compound of formula (XXXVII) can be synthesized in asimilar manner, either directly by an amide coupling of Intermediate 1with an amine of formula (XI), or amide coupling with an aryl chlorideof formula (XIV) followed by a fluorination reaction. For instance, anamide coupling of Intermediate 1 with an amine of formula (XI), in amanner previously described, provides a compound of formula (XXXVII),where b is 0 or 1; c is 1 or 2; and B, D, E and G are C or N.Alternatively, amide coupling of Intermediate 1 with an amine of formula(XIV), under conditions previously described, provides an aryl chlorideof formula (XXXVI), where b is 0 or 1; c is 1 or 2; and B, D, E and Gare C or N. A subsequent fluorination reaction of the aryl chloride,under conditions known to one of skill in the art, such as treatmentwith potassium fluoride, in a solvent such as DMSO or the like, at atemperature ranging from 100° C. to 200° C., sometimes 170° C., providesa compound of formula (XXXVII).

An aryl amine of formula (XXXVIII) can be synthesized directly throughan amide coupling or in two steps by an amide coupling followed bynucleophilic aromatic substitution of the resulting aryl chloride. Forexample, treatment of Intermediate 1 with an amine of formula (XIII) inan amide coupling reaction, under conditions previously described,provides an amine of formula (XXXVIII), where b is 0 or 1; c is 1 or 2;and B, D, E and G are C or N; and R⁴ and R⁵ are independently H or anoptionally substituted C₁₋₆alkyl or C₃₋₇cycloalkyl group, or R⁴ and R⁵come together to form an optionally substituted N-containingheterocycloalkyl group. Alternatively, an amide coupling with an arylchloride of formula (XIV), followed by a nucleophilic aromaticsubstitution reaction with a commercially available or syntheticallyaccessible amine, in the presence of a base such as potassium carbonate,or the like, in a solvent such as ACN, at a temperature ranging from 40°C. to 100° C., sometimes 80° C., also provides a compound of formula(XXXVIII).

Various amide analogs can be synthesized from Intermediate 1, as shownin Scheme I.

An oxygen substituted compound of formula (XLIII) is afforded either byamide coupling of Intermediate 1 with an amine of formula (XXVI), thesynthesis of which is described in Scheme F, or by an initial amidecoupling with ethyl 3-oxopiperidine-4-carboxylate, followed by athree-step conversion to desired product. For example, amide coupling ofIntermediate 1 with a commercially available or synthetically accessibleamine of formula (XXVI), under conditions previously described, providesa compound of formula (XLIII), where R⁸ is H or an optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group, and R⁹ isH or an optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl orC₃₋₇cycloalkyl group. Alternatively, treatment of Intermediate 1 withethyl 3-oxopiperidine-4-carboxylate in an amide coupling reaction, underconditions previously described, provides ethyl1-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-3-oxopiperidine-4-carboxylate.Subsequent treatment with a substituted amidine, in the presence of abase such as sodium ethoxide or the like, in a solvent such as ethanol,at a temperature ranging from 40° C. to 100° C., sometimes 90° C.,provides a tetrahydropyridopyrimidinone of formula (XLI), where R⁸ is Hor an optionally substituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkylgroup. Chlorination using conditions known to one of skill in the art,for example using carbon tetrachloride in the presence oftriphenylphosphine, in a solvent such as dichloroethane or the like, ata temperature of 70° C., provides an aryl chloride of formula (XLII). Anucleophilic aromatic substitution reaction with an alkoxide, in asolvent such as THF, or the like, at a temperature ranging from 60° C.to 100° C., sometimes 90° C., also provides a compound of formula(XLIII).

In another embodiment, treatment of Intermediate 1 with an amine offormula (XXVII), under conditions previously described, provides anitrile compound of formula (XL), where R⁸ is H or an optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl or C₃₋₇cycloalkyl group. In asimilar manner, treatment of Intermediate 1 with an amine of formula(XXII), under conditions previously described, provides a compound offormula (XXXIX), where R⁸ is H or an optionally substituted C₁₋₆alkyl,C₁₋₆haloalkyl or C₃₋₇cycloalkyl group, and R¹⁰, R¹¹ and R¹² areindependently H or C₁₋₆alkyl or R¹⁰ and R¹¹ taken together can form anoptionally substituted saturated C₃₋₆cycloalkyl or saturatedC₃₋₆heterocycloalkyl group.

According to Scheme J, an amide coupling of a compound of Intermediate 1and a 1,3-substituted-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine offormula (XLIV), under conditions previously described, provides acompound of formula (XLV), where R¹⁵ and R¹⁶ are an optionallysubstituted C₁₋₆alkyl, C₁₋₆haloalkyl, or C₃₋₆cycloalkyl group.

An amide of formula (XXXII) can be synthesized in two steps fromIntermediate 2, by an amide coupling with a commercially available orsynthetically accessible amine, followed by a nucleophilic aromaticsubstitution reaction with 1-methylcyclopropan-1-amine hydrochloride.For instance, an amide coupling reaction of a carboxylic acid ofIntermediate 2 with an amine, under conditions previously described,provides an amide of formula (XLVI), where R¹³ and R¹⁴ are independentlyH, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₄alkylaryl, or C₁₋₄alkyl-heteroaryl; orR¹³ and R¹⁴ come together to form an optionally substituted N-containingheterocycloalkyl group or an optionally substituted N-containingheteroaryl group. Subsequently, treatment with1-methylcyclopropan-1-amine hydrochloride, in the presence of a basesuch as triethylamine, or the like, and a solvent such as IPA, providesan amide of formula (XXXII).

EXAMPLES Chemistry

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under an atmosphere of nitrogen. Where solutionswere “dried,” they were generally dried over a drying agent such asNa₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were“concentrated,” they were typically concentrated on a rotary evaporatorunder reduced pressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on Silica(SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

Analytical LC/MS were obtained on a Waters 2695 Separations Unit, 2487Dual Absorbance Detector, Micromass ZQ fitted with ESI Probe, or aWaters Acquity™ Ultra performance LC (UPLC) with PDA eλ and SQdetectors. Alternatively, LC-MS was performed on a Waters AcquityUPLC-MS instrument equipped with a Acquity UPLC BEH C18 column (1.7 µm,2.1 × 50 mm) and the solvent system A: 0.1% HCOOH in H₂O and B: 0.1%HCOOH in ACN. Column temperature was 45° C. All compounds were run usingthe same elution gradient, i.e., 5% to 95% solvent B in 0.75 min with aflow rate of 1 mL/min.

Analytical SFC-MS was performed on a Waters UPC²-MS instrument equippedwith a Acquity UPC² BEH 2-ethylpyridine column (1.7 µm, 2.1 × 50 mm) andthe solvent system A: CO₂ and B: 0.1% NH₄OH in MeOH. Column temperaturewas 55° C. All compounds were run using the same elution gradient, i.e.,3% to 35% solvent B in 0.75 min with a flow rate of 2.5 mL/min.

Preparative HPLC was performed on a Shimadzu SIL-10AP system using aWaters SunFire™ OBD (5 µm, 30 × 100 mm) C18 column with a 15-minutegradient of 10-100% acetonitrile in water and 0.05% trifluoroacetic acidadded as a modifier to both phases. Elution profiles were monitored byUV at 254 and 220 nm.

Some compounds were purified using a Waters Fractionlynx system equippedwith a XBridge Prep C18 OBD column (5 µm, 19×50 mm) and the solventsystem: H₂O:AcCN and 2% TFA in H₂O. Specific elution gradients werebased on retention times obtained with an analytical UPLC-MS, however,in general all elution gradients of H₂O and ACN were run over a 5.9 minrun time with a flow rate of 40 mL/min. An autoblend method was used toensure a concentration of 0.1% TFA throughout each run.

Some compounds were purified using a Waters Fractionlynx system equippedwith a XBridge Prep C18 OBD column (5 µm, 30×100 mm) and the solventsystem: H₂O:AcCN and 2% TFA in H₂O. Specific elution gradients werebased on retention times obtained with an analytical UPLC-MS, however,in general all elution gradients of H₂O and ACN were run over a 9 minrun time with a flow rate of 60 mL/min. An autoblend method was used toensure a concentration of 0.1% TFA throughout each run.

Preparative SFC-MS was run on a Waters Prep100 SFC-MS system equippedwith a Viridis 2-ethylpyridine OBD column (5 µm, 30 × 100 mm) and thesolvent system: CO₂:MeOH and 0.2% NH₄OH in MeOH as a co-solvent.Specific elution gradients were based on retention times obtained withan analytical UPC²-MS, however, in general all elution gradients of CO₂and MeOH were run over a 3.6 min run time with a flow rate of 100 mL/minand a column temperature of 55° C. An autoblend method was used toensure a concentration of 0.2% NH₄OH throughout each run.

Nuclear magnetic resonance (NMR) spectra were obtained in an Agilent 300MHz VNMR (Varian 300 MHz NMR) or a Varian 400 MHz or Bruker 400 MHz NMR.Samples were analyzed in either deuterated acetone ((CD₃)₂CO),chloroform (CDCl₃), MeOH-d₄ (CD₃OD), N,N-dimethylformamide-d₇ (DMF-d₇)or dimethyl sulfoxide-d₆ (DMSO-d₆). For (CD₃)₂CO samples, the residualcentral resonance peak at 2.05 for ¹H was used for chemical shiftassignment for ¹H NMR spectra. For CDCl₃ samples, the residual centralresonance peak at 7.26 for ¹H was used for chemical shift assignment for¹H NMR spectra. For CD₃OD the residual central resonance peak at 3.31for ¹H was used for chemical shift assignment and for DMF-d₇ theresidual central resonance peaks at 2.92 or 2.75 for ¹H were used forchemical shift assignment. For DMSO-d₆ the residual central resonancepeak at 2.50 ppm for ¹H was used for chemical shift assignment. Theformat of the ¹H NMR data below is: chemical shift in ppm downfield thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration), using conventional abbreviations for designation of majorpeaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; p, pentet;m, multiplet; br, broad.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, MA), ChemDraw Professional 15.1 (CambridgeSoft Corp.,Cambridge, MA) or ChemAxon.

Intermediate 1.6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo[2,3-d]Pyrimidine-5-CarboxylicAcid

Step 1. Ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate. Sodiumethoxide (2.49 L, 21 %w/w, 6.68 mol) was diluted with ethyl alcohol(3.00 L). The jacket temperature was set to -10° C. Separately, asolution of ethyl 2-chloro-3-oxobutanoate (840 mL, 6.08 mol) andmalononitrile (401 g, 6.08 mol) were taken up in ethanol (2.00 L). Thesubstrate solution was added, maintaining the internal temperature below10° C. Upon complete addition, the jacket temperature was adjusted to10° C. and the slurry was stirred overnight. A total of 2.90 L ofsolvent was removed by vacuum distillation. The temperature was thenramped to 45° C. and water (10 L) was charged to the reactor. The slurrywas stirred overnight and cooled to 11° C. The solid was collected byvacuum filtration and then slurried/washed with additional water (10 L).The solid was air dried to afford the title product (1.058 kg, 90%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.42 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.37(s, 3H), 1.26 (t, J = 7.2 Hz, 3H). [M+H] = 195.

Step 2. Ethyl 4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate.Formic acid (700 mL) was charged to a 5 L reactor, and then ethyl5-amino-4-cyano-2-methylfuran-3-carboxylate (292 g, 1.50 mol) was addedas a solid followed by additional formic acid (1.46 L). This mixture wascooled to 0° C. and acetic anhydride (1,752 mL, 6.0 V) was addeddrop-wise maintaining the internal temperature below 10° C. (additionwas over 2 h). The reaction was warmed gradually until the jackettemperature reached 100° C. (internal temperature observed to be 97.5°C.). The reaction was held at this temperature overnight. After 48 h,the jacket temperature was cooled to 65° C. and 2.3 L of solvent wasremoved by vacuum distillation. The reactor was cooled and when theinternal temperature was approximately 60° C., water (2.92 L) was addedover 15 min and the reaction was stirred at this temperature for 2 huntil solids become uniform. The slurry was then cooled to 10° C. andheld overnight. The solids were collected by filtration and washed withwater (5.84 L). After an additional rinse with water (1.80 L), the solidcake was packed down then rinsed with heptane (300 mL). The solid cakewas dried on the funnel for 5 h and then dried in the vacuum oven toprovide the title compound as an off-white solid (285 g, 85%). ¹H NMR(400 MHz, CDCl₃) δ 8.19 (s, 1H), 4.42 (q, J = 8.0 Hz, 2H), 2.71 (s, 3H),1.43 (t, J = 8.0 Hz, 3H). [M+H] = 223.

Step 3. Ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. In a5 L vertical reactor was added ethyl4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate (252 g, 1.13 mol)and ACN (2.52 L). At room temperature, phosphorus oxychloride (212 mL,2.27 mol) was added. The internal reaction temperature was brought to 0°C., then DIEA (198 mL, 1.13 mol) was added slowly. Upon completeaddition, the jacket temperature was raised to 85° C. and the reactionwas allowed to stir at that temperature. After 4 h, the reaction wasjudged complete by UPLC analysis. A portion of the ACN solvent (1.10 L)was removed by vacuum distillation. The internal reaction temperaturewas cooled to 0° C., cold water (2.52 L) was charged into the reactorand the mixture was stirred at 0° C. overnight. The slurry was filteredand rinsed with cold water (5.04 L) to give a tan solid. This materialwas dried overnight to afford the title compound (216 g, 79%). ¹H NMR(400 MHz, CDCl₃) δ 8.80 (s, 1H), 4.43 (q, J = 8.0 Hz, 2H), 2.80 (s, 3H),1.45 (t, J = 8.0 Hz, 3H). [M+H] = 241.

Step 4. Ethyl6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate.1-Methylcyclopropanamine hydrochloride (124 g, 1.09 mol) was taken up inIPA (800 mL). Ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate(203 g, 0.84 mol) was added, followed by additional IPA (800 mL). TEA(352 mL, 2.53 mol) was added slowly at ambient temperature. The reactionwas warmed to 45° C. and stirred overnight. Once the reaction was judgedto be complete, water (2.40 L) was added over 30 minutes, thetemperature was lowered to 10° C. and the reaction was stirred for 3 h.The solids were filtered, washed with water (2.40 L) and dried to affordthe title compound (194 g, 84%). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (br s,1H), 8.45 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.56 (s, 3H),1.44 (t, J = 7.1 Hz, 3H), 0.91 - 0.71 (m, 4H). [M+H] = 276.

Step 5.6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid. Ethyl6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate(128 g, 0.46 mol) was dissolved in THF (1.24 L) and lithium hydroxide(1.5 M, 1.24 L, 1.86 mol) was added slowly, followed by methanol (256mL). The reaction was stirred at ambient temperature for 1.5 h. Uponreaction completion, a mixture of methanol/THF (~1.4 L) was removed byvacuum distillation. The reactor temperature was returned to 20° C. andwater (1.92 L) was charged into the system. An addition funnelcontaining hydrochloric acid (12.1 M, 154 mL, 1.86 mol) was equipped tothe reactor. The acid was added dropwise until reaching pH<4 duringwhich time a white precipitate began to form. The slurry was stirred atambient temperature for 1 h after the addition and then vacuum filtered.This solid was rinsed with water (1.92 L) and dried on the filter for anadditional 2 h. The solid was then slurried in water (3.5 L) at 70° C.The solution was filtered and rinsed with ACN (4 × 1 L) and thenpressed/packed and allowed to dry to provide the title compound (104 g,90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.87 (br s, 1H),8.33 (s, 1H), 2.68 (s, 3H), 1.46 (s, 3H), 0.73 (s, 4H). [M+H] = 248.

Intermediate 2 4-Chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic Acid

Aqueous lithium hydroxide (25 mL, 1.00 M, 25 mmol) was added to asolution of ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate(1.00 g, 4.16 mmol) in tetrahydrofuran (14 mL) and the mixture wasstirred for 1 h. The mixture was acidified to pH 1 with concentratedhydrochloric acid (3 mL) and extracted twice with ethyl acetate. Thecombined organic extracts were washed with brine, dried (MgSO₄) andconcentrated to provide the product as a yellow solid, which was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (br s,1H), 8.81 (s, 1H), 2.70 - 2.77 (m, 3H). [M+H] = 213.1.

Intermediate 3 4-Fluoro-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineHydrochloride

Step 1. tert-Butyl4-fluoro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. A mixtureof tert-butyl4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (200 mg,0.74 mmol) and cesium fluoride (169 mg, 1.11 mmol) in DMSO (3.7 mL) washeated at 70° C. for 3 h. The reaction mixture was diluted with methanoland was purified by preparative HPLC (elution with 10-60% ACN in watercontaining 0.05% TFA). Fractions containing product were combined,diluted with an aqueous solution of NaHCO₃ and extracted with ethylacetate. Combined organics were dried over MgSO₄ and concentrated toafford the title compound (67 mg, 37%) as a yellow semi-solid. [M+H] =254.1.

Step 2. 4-Fluoro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride. tert-Butyl4-fluoro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (67 mg,0.24 mmol) was dissolved in a solution of hydrogen chloride in dioxane(4 M, 0.62 mL, 2.5 mmol). The mixture was stirred for 30 min and thenconcentrated under vacuum to afford the title compound (46 mg, 100%) asa yellow solid.

Intermediate 4.3-Fluoro-5-(1,2,3,6-Tetrahydropyridin-4-yl)Pyridine-2-Carbonitrile

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.02 g, 3.30 mmol) and 5-bromo-3-fluoropyridine-2-carbonitrile (0.60 g,3.0 mmol) were combined and dissolved in dioxane (7 mL) and ethanol (3mL) and nitrogen gas was bubbled through the mixture. Water (2 mL),aqueous potassium carbonate (2.0 M, 4.5 mL, 9.0 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were addedand the mixture was heated at 150° C. for ten minutes in a microwavereactor. Much of the tert-butoxycarbonyl protecting group was alsocleaved at this temperature. The mixture was poured into ethyl acetate(30 mL), the aqueous layer was removed and the organic layer was washedwith brine (20 mL). The solution was then dried (MgSO₄) and concentratedunder vacuum to afford a mixture of the title compound and thetert-butoxycarbonyl-protected title compound (0.36 g). [M+H] = 204.1.

Intermediate 5.5-Fluoro-6-methoxy-1',2',3',6′-Tetrahydro-3,4′-BipyridineTrifluoroacetate

Step 1. tert-Butyl4-(5-fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate.tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.02 g, 3.30 mmol) and 5-bromo-3-fluoro-2-methoxypyridine (0.62 g, 3.00mmol) were combined and dissolved in dioxane (7 mL) and ethanol (3 mL)and nitrogen gas was bubbled through the mixture. Water (2 mL), aqueouspotassium carbonate (2.0 M, 4.5 mL, 9.00 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were addedand the mixture was heated at 150° C. for 10 min by microwave. Themixture was poured into ethyl acetate (30 mL), the aqueous layer wasremoved and the organic layer was washed with brine (20 mL), dried(MgSO₄) and concentrated under vacuum. The residue was purified by flashchromatography (elution with 5-30% ethyl acetate in heptane) to affordthe title compound (0.28 g, 30%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.96 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 2.0, 11.4 Hz, 1H), 6.00(br s, 1H), 4.10 (d, J = 2.8 Hz, 2H), 4.05 (s, 3H), 3.66 (t, J = 5.7 Hz,2H), 2.49 (br s, 2H), 1.51 (s, 10H). [M+H] = 309.0.

Step 2. 5-Fluoro-6-methoxy-1′,2′,3′,6′-tetrahydro-3,4′-bipyridinetrifluoroacetate. tert-Butyl4-(5-fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate(280 mg, 0.91 mmol) was stirred in a mixture of DCM (3 mL) and TFA (3mL) for 1 h and then concentrated under vacuum to afford the titlecompound (574 mg, 100%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ8.94 (br s, 2H), 8.12 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.1, 12.2 Hz,1H), 6.27 (br s, 1H), 3.96 (s, 3H), 3.82 - 3.72 (m, 2H), 3.34 (d, J =5.6 Hz, 2H), 2.72 - 2.64 (m, 2H). [M+H] = 209.1.

Intermediate 6 2-(2,5-Dihydro-1H-Pyrrol-3-yl)-5-FluoropyrimidineTrifluoroacetate

Step 1. tert-butyl3-(5-fluoropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 5,Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.59 (s, 2H), 6.96 -6.75 (m, 1H), 4.59 (br s, 2H),4.43 (br s, 2H), 1.54 (s, 9H). [M+H] = 266.1.

Step 2. 2-(2,5-Dihydro-1H-pyrrol-3-yl)-5-fluoropyrimidinetrifluoroacetate. The title compound was prepared in a manner analogousto Intermediate 5, Step 2 using the appropriate starting materialsubstitutions. [M+H] was not observed.

Intermediate 7.2-(1,2,3,6-Tetrahydropyridin-4-yl)Pyrimidine-4-CarbonitrileTrifluoroacetate

Step 1. tert-Butyl4-(4-cyanopyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 5,Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.91 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H),7.37 (br s, 1H), 4.23 (d, J = 2.6 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H),2.72 (br s, 2H), 1.52 (s, 9H). [M+H-t-Bu] = 231.1.

Step 2. 2-(1,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-4-carbonitriletrifluoroacetate. The title compound was prepared in a manner analogousto Intermediate 5, Step 2 using the appropriate starting materialsubstitutions. ¹H NMR (400 MHz, CD₃OD) δ 9.09 - 8.97 (m, 1H), 8.38 -8.35 (m, 1H), 7.94 (dd, J = 5.0, 13.0 Hz, 1H), 7.50 - 7.34 (m, 1H),4.06 - 3.96 (m, 3H), 3.79 - 3.57 (m, 1H), 3.14 - 2.95 (m, 2H). [M+H] =187.1.

Intermediate 8.(R)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-Tetrahydropyrido[3,4-DlpyrimidineHydrochloride

Step 1. (R)-tert-Butyl4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.tert-Butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(226 mg, 0.84 mmol) in DMA (2.5 mL) was treated with(3R)-3-fluoropyrrolidine (1.58 g, 1.26 mmol) and DIEA (0.44 mL, 2.51mmol) and the mixture was heated at 80° C. for 16 h. The mixture wascooled, concentrated under vacuum and the residue was purified by flashLC (elution with 0-75% A in B, where A is 10% methanol in ethyl acetateand B is heptane) to afford the title compound (212 mg, 78%) as acolorless semi-solid. [M+H] = 323.1.

Step 2.(R)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride. (R)-tert-Butyl4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(212 mg, 0.66 mmol) was dissolved in ethyl acetate (6 mL) and treatedwith hydrogen chloride in dioxane (4 M, 1.97 mL, 7.89 mmol). The mixturewas stirred for 24 h and was then concentrated under vacuum to affordthe title compound (192 mg, 99%) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.65 (s, 1H), 5.58 - 5.33 (m, 1H), 4.47 (s, 2H), 4.40 - 4.04(m, 4H), 3.76 - 3.69 (m, 1H), 3.56 - 3.35 (m, 3H), 2.54 - 2.12 (m, 2H).[M+H] = 223.1.

Intermediate 9.(S)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-dlpyrimidineHydrochloride.

Step 1. (S)-tert-Butyl4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate 8,Step 1 using the appropriate starting material substitutions. LCMS datawas identical to that of Intermediate 8.

Step 2.(S)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride. The title compound was prepared in a manner analogous toIntermediate 8, Step 2 using the appropriate starting materialsubstitutions. LCMS and ¹H NMR data were identical to that ofIntermediate 8.

Intermediate 104-(5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidin-4-yl)Morpholine

Step 1. tert-Butyl4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 8,Step 1 using the appropriate starting material substitutions. [M+H] =321.1.

Step 2. 4-(5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine. Thetitle compound was prepared in a manner analogous to Intermediate 8,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.69 (s, 1H), 4.50 (s, 2H), 4.13 -4.01 (m, 4H),3.89 - 3.80 (m, 4H), 3.52 (t, J = 5.7 Hz, 2H), 3.15 (t, J = 5.7 Hz, 2H).[M+H] = 221.1.

Intermediate 114-(3-Fluoroazetidin-1-yl)-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-(3-fluoroazetidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate 8,Step 1 using the appropriate starting material substitutions. [M+H] =309.0.

Step 2.4-(3-Fluoroazetidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thetitle compound was prepared in a manner analogous to Intermediate 8,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.64 (s, 1H), 5.66-5.41 (m, 1H), 4.99 (br s, 2H),4.73 (br s, 2H), 4.43 (s, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.17 (t, J =6.1 Hz, 2H). [M+H] = 209.1.

Intermediate 12. 2-Fluoro-4-(Pyrrolidin-3-yl)Pyridine Hydrochloride

Step 1. tert-Butyl3-(2-fluoropyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.tert-Butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(434 mg, 1.47 mmol), 4-bromo-2-fluoropyridine (311 mg, 1.76 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54 mg, 0.07mmol) and dioxane (23 mL) were combined. Aqueous sodium bicarbonate (1.2M, 7.7 ml, 8.8 mmol) was added and the mixture was heated at 100° C. for24 h. The mixture was cooled and diluted with ethyl acetate (75 mL) andbrine (25 mL) and the layers were separated. The organic layer was dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography (elution with 0-75% ethyl acetate in heptane) to affordthe title compound (341 mg, 88%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.41 (d, J = 5.3 Hz, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.23 - 7.13(m, 1H), 6.86 (br s, 1H), 6.53 - 6.40 (m, 1H), 4.50 (dd, J = 3.6, 19.3Hz, 2H), 4.38 (d, J = 18.5 Hz, 2H), 1.55 -1.52 (m, 9H). [M+H] = 265.1.

Step 2. 2-Fluoro-4-(pyrrolidin-3-yl)pyridine hydrochloride. A solutionof tert-Butyl3-(2-fluoropyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (251 mg,0.95 mmol) in methanol (7.5 mL) and ethyl acetate (7.5 mL) was flushedwith nitrogen and palladium on activated carbon (81 mg, 0.38 mmol) wasadded. The mixture was stirred rapidly under a balloon of hydrogen for 3h. The mixture was flushed with nitrogen, filtered through a pad ofCelite® and concentrated under vacuum. The residue was suspended inethyl acetate (5 mL) and a solution of hydrochloric acid in dioxane (4M, 5.0 mL, 5.0 mmol) was added. The mixture was stirred for 1 h andconcentrated under vacuum. The residue was taken up in a 1:1 mixture ofdioxane-water and lyophilized to afford the title compound (294 mg, 90%)as a brown semi-solid. ¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J = 5.3 Hz,1H), 7.37 - 7.30 (m, 1H), 7.13 (s, 1H), 3.91 - 3.54 (m, 5H), 3.54 - 3.39(m, 2H), 2.24 - 2.10 (m, 1H). [M+H] = 167.2.

Intermediate 13. 2-Fluoro-4-Methyl-6-(Pyrrolidin-3-yl)PyridineHydrochloride

Step 1. tert-Butyl4-(6-fluoro-4-methylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.The title compound was prepared in a manner analogous to Intermediate12, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 7.11 - 6.84 (m, 1H), 6.67 (s, 1H), 6.65 - 6.51 (m,1H), 4.53 (br s, 2H), 4.42 - 4.29 (m, 2H), 2.42 (d, J = 4.9 Hz, 3H),1.56 - 1.51 (m, 9H). [M+H] was not observed.

Step 2. 2-Fluoro-4-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride. Thetitle compound was prepared in a manner analogous to Intermediate 12,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 7.16 (s, 1H), 6.82 (s, 1H), 3.81 - 3.48 (m, 4H),3.48 - 3.36 (m, 1H), 2.56 - 2.38 (m, 4H), 2.26 - 2.11 (m, 1H). [M+H] =181.1.

Intermediate 14. 3-Fluoro-2-Methyl-6-(Pyrrolidin-3-yl)PyridineHydrochloride

Step 1. tert-Butyl4-(5-fluoro-6-methylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.The title compound was prepared in a manner analogous to Intermediate12, Step 1 using the appropriate starting material substitutions.[M+H-tert-butyl] = 223.1.

Step 2. 3-Fluoro-2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride. Thetitle compound was prepared in a manner analogous to Intermediate 12,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.09 (t, J = 8.7 Hz, 1H), 7.78 (dd, J = 4.0, 8.8 Hz,1H), 3.97 (quin, J = 8.2 Hz, 1H), 3.81 (dd, J = 8.3, 11.8 Hz, 1H),3.73 - 3.54 (m, 2H), 3.48 (td, J = 8.1, 11.5 Hz, 1H), 2.71 (d, J = 2.6Hz, 3H), 2.68 - 2.54 (m, 1H), 2.31 (qd, J = 8.7, 13.2 Hz, 1H). [M+H] =181.1.

Intermediate 15. 5-Fluoro-4-Methyl-2-(Pyrrolidin-3-yl)PyrimidineHydrochloride

Step 1. tert-Butyl4-(5-fluoro-4-methylpyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.The title compound was prepared in a manner analogous to Intermediate12, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.41 (s, 1H), 6.91 - 6.74 (m, 1H), 4.67 - 4.47 (m,2H), 4.47 - 4.30 (m, 2H), 2.60 - 2.48 (m, 3H), 1.59 - 1.47 (m, 9H).[M+H-tert-butyl] = 224.1.

Step 2. 3-Fluoro-2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride. Thetitle compound was prepared in a manner analogous to Intermediate 12,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.60 (d, J = 1.8 Hz, 1H), 3.97 - 3.84 (m, 1H), 3.80 -3.74 (m, 1H), 3.72 - 3.64 (m, 1H), 3.54 - 3.41 (m, 2H), 2.61 - 2.47 (m,4H), 2.33 (qd, J = 6.7, 13.8 Hz, 1H). [M+H] = 182.1.

Intermediate 16. 2-(Pyrrolidin-3-yl)-6-(trifluoromethyl)pyridineHydrochloride

Step 1. tert-Butyl4-(6-(trifluoromethyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.The title compound was prepared in a manner analogous to Intermediate12, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 7.86 (t, J = 7.9 Hz, 1H), 7.63 - 7.40 (m, 2H), 6.68(d, J = 18.0 Hz, 1H), 4.61 (d, J = 15.3 Hz, 2H), 4.51 - 4.29 (m, 2H),1.54 (d, J = 7.1 Hz, 9H). [M+H-tert-butyl] = 259.1.

Step 2. 2-(Pyrrolidin-3-yl)-6-(trifluoromethyl)pyridine hydrochloride.The title compound was prepared in a manner analogous to Intermediate12, Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.05 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H),7.68 (d, J = 7.8 Hz, 1H), 3.91 (quin, J = 7.7 Hz, 1H), 3.80 - 3.63 (m,2H), 3.63 - 3.53 (m, 1H), 3.46 (td, J = 7.8, 11.5 Hz, 1H), 2.62 - 2.47(m, 1H), 2.32 - 2.18 (m, 1H). [M+H] = 217.2.

Intermediate 17. 2-(Pyrrolidin-3-yl)-4-(Trifluoromethyl)PyridineHydrochloride

Step 1. tert-Butyl4-(4-(trifluoromethyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate.The title compound was prepared in a manner analogous to Intermediate12, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.78 (d, J = 5.0 Hz, 1H), 7.69 - 7.48 (m, 1H), 7.48 -7.38 (m, 1H), 6.66 (br s, 1H), 4.68 - 4.56 (m, 2H), 4.49 -4.34 (m, 2H),1.56 - 1.52 (m, 9H), 1.56 - 1.52 (m, 9H). [M+H-tert-butyl] = 259.3.

Step 2. 2-(Pyrrolidin-3-yl)-4-(trifluoromethyl)pyridine hydrochloride.The title compound was prepared in a manner analogous to Intermediate12, Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 8.86 (d, J = 5.3 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J =5.1 Hz, 1H), 3.97 (quin, J = 7.2 Hz, 1H), 3.72 - 3.66 (m, 2H), 3.64 -3.53 (m, 1H), 3.47 (td, J = 7.6, 11.6 Hz, 1H), 2.58 (dtd, J = 6.1, 7.6,13.4 Hz, 1H), 2.31 - 2.19 (m, 1H). [M+H] = 217.2.

Intermediate 18 4-Ethyl-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineHydrochloride

Step 1. tert-Butyl4-vinyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. A mixtureof tert-butyl4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (500 mg,1.85 mmol), potassium vinyltrifluoroborate (372 mg, 2.78 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex withdichloromethane (76 mg, 0.09 mmol), ACN (7.4 mL), and aqueous sodiumbicarbonate (1 M, 3.3 mL, 3.3 mmol) was degassed for 1 min with nitrogenand then heated to 90° C. for 2 h. The mixture was filtered throughCelite®, diluted with ethyl acetate, washed with brine, dried (MgSO₄)and concentrated to a red oil. This material was adsorbed onto silicausing DCM and flash chromatography (elution with 0-25% ethyl acetate inheptane) afforded the title compound (300 mg, 62%) as an oil. ¹H NMR(400 MHz, CDCl₃) δ 8.97 (s, 1H), 6.91 (dd, J = 10.64, 16.87 Hz, 1H),6.68 (dd, J = 1.83, 16.99 Hz, 1H), 5.77 (dd, J = 1.83, 10.64 Hz, 1H),4.65 (s, 2H), 3.75 (t, J = 5.87 Hz, 2H), 2.89 (t, J = 5.75 Hz, 2H), 1.51(s, 9H). [M+H] = 262.2.

Step 2. tert-Butyl4-ethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. tert-Butyl4-vinyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (293 mg,1.12 mmol) and 10% palladium on carbon (60 mg, 0.056 mol) in ethylacetate (3.7 mL) and methanol (3.7 mL) were stirred under 180 psi ofhydrogen for 16 h. The catalyst was filtered and the filtrateconcentrated to afford the title compound (269 mg, 91%) as a solid. ¹HNMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 4.63 (s, 2H), 3.74 (t, J = 5.8 Hz,2H), 2.86 - 2.72 (m, 4H), 1.51 (s, 9H), 1.31 (t, J = 7.5 Hz, 3H). [M+H]= 264.2.

Step 3. 4-Ethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.To a stirring solution of tert-butyl4-ethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (269 mg,1.0mmol) in dioxane (5.1 mL) was added a solution of hydrogen chloride indioxane (4 M, 1.28 mL, 5.1 mmol) and the solution was stirred for 18 h.The mixture was concentrated and the residue was taken up andconcentrated twice from methanol and twice from DCM to afford the titlecompound (222 mg, 100%) as a solid.

Intermediate 19.4-(Tetrahydro-2H-Pyran-4-yl)-5,6,7,8-Tetrahydropyrido[3,4-DlpyrimidineHydrochloride

Step 1. tert-Butyl4-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate18, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 9.01 (s, 1H), 8.99 (s, 1H), 6.10 (br s, 1H), 5.96 (s,1H), 5.66 (d, J = 2.20 Hz, 1H), 4.68 (s, 3H), 4.37 (q, J = 2.69 Hz, 2H),3.96 (t, J = 5.32 Hz, 2H), 3.67 (t, J = 5.56 Hz, 2H), 2.92 (t, J = 5.32Hz, 2H), 2.59 (dd, J = 2.57, 4.40 Hz, 2H), 1.52 (s, 13H), 1.29 (s, 2H),1.26 (s, 1H. [M+H] = 318.2.

Step 2. tert-Butyl4-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate18, Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.97 (s, 1H), 4.64 (s, 2H), 4.12 (dd, J = 3.6, 11.2Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.62 - 3.50 (m, 2H), 3.06 (tt, J =3.5, 11.6 Hz, 1H), 2.86 (t, J = 5.7 Hz, 2H), 2.18 - 2.02 (m, 2H), 1.63(dd, J = 1.6, 13.2 Hz, 2H), 1.51 (s, 9H). [M+H-tert-butyl] = 320.3.

Step 3.4-(Tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride. The title compound was prepared in a manner analogous toIntermediate 18, Step 3 using the appropriate starting materialsubstitutions. ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (br s, 2H), 8.99 (s,1H), 4.26 (t, J = 4.59 Hz, 2H), 3.96 (dd, J = 3.42, 11.25 Hz, 2H),3.47 - 3.55 (m, 2H), 3.43 (d, J = 6.97 Hz, 2H), 3.17 (tt, J = 3.59,11.51 Hz, 1H), 3.10 (t, J = 6.05 Hz, 2H), 1.83 (dq, J = 4.34, 12.41 Hz,2H), 1.60 (d, J = 11.25 Hz, 2H). [M+H] = 220.2.

Intermediate 20.4-(Prop-1-en-2-yl)-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineTrifluoroacetate

Step 1. tert-Butyl4-(prop-1-en-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate18, Step 1 using potassium trifluoro(prop-1-en-2-yl)borate and anyappropriate starting material substitutions. [M+H] = 276.3.

Step 2. 4-(Prop-1-en-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinetrifluoroacetate. The title compound was prepared in a manner analogousto Intermediate 18, Step 3 using any appropriate starting materialsubstitutions. [M+H] = 176.1.

Intermediate 21. 4-Cyclopropyl-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineTrifluoroacetate

Step 1. tert-Butyl4-cyclopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 18,Step 1 using cyclopropylboronic acid and any appropriate startingmaterial substitutions. [M+H] = 276.3.

Step 2. 4-Cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinetrifluoroacetate. The title compound was prepared in a manner analogousto Intermediate 18, Step 3 using any appropriate starting materialsubstitutions. [M+H] = 176.1.

Intermediate 22 5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine-4-Carbonitrile

Step 1. tert-Butyl4-cyano-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. A mixtureof tert-butyl4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500 mg,1.85 mmol), DMF (10 mL), dicyanozinc (272 mg, 2.32 mmol) andtetrakis(triphenylphosphine)palladium(0) (214 mg, 0.19 mmol) wasdegassed by bubbling nitrogen through the mixture for 1 min then themixture was heated at 90° C. for 2 h. The mixture was diluted with ethylacetate, filtered through Celite®, washed with water and brine, dried(MgSO₄) and concentrated. The residue was adsorbed to silica andpurified by flash chromatography (elution with 0-25% ethyl acetate inheptane) to provide the title compound (374 mg, 78%). ¹H NMR (400 MHz,CDCl₃) δ 9.14 (s, 1H), 4.74 (s, 2H), 3.81 (t, J = 5.87 Hz, 2H), 3.08 (t,J = 5.75 Hz, 2H), 1.52 (s, 9H).

Step 2. 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile.tert-Butyl 4-cyano-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(20 mg, 0.08 mmol) was dissolved in DCM (0.20 mL) and TFA (0.20 mL) andthe mixture was stirred for 1 h. It was diluted with DCM and washed with1 M Na₂CO₃. The aqueous layer was extracted with 10% methanol in DCM,and the combined organics were dried (MgSO₄) and concentrated to affordthe title compound (4.0 mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s,1H), 4.15 (s, 2H), 3.26 (t, J = 5.87 Hz, 2H), 3.04 (t, J = 5.69 Hz, 2H),2.07 (br s, 2H). [M+H] = 161.3.

Intermediate 23 4-Ethoxy-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-ethoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.tert-Butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate(700 mg, 2.60 mmol) was dissolved in tetrahydrofuran (7 mL). Sodiumethoxide (25% w/w, 1.12 mL, 3.9 mmol) was added and stirring wascontinued for 15 min. The reaction was quenched with aqueous ammoniumchloride (3.5 mL) and water (20 mL) and extracted with ethyl acetate (3× 20 mL). The combined organics were dried (MgSO₄), concentrated and theresidue was purified by flash chromatography (elution with 0-60% ethylacetate in heptane) to afford the title compound (729 mg, 100%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 5.32 (s, 1H), 4.56(s, 2H), 4.47 (q, J = 7.05 Hz, 2H), 3.69 (t, J = 5.81 Hz, 2H), 2.70 (t,J = 5.38 Hz, 2H), 1.51 (s, 9H), 1.42 (s, 3H). [M+H] = 280.0.

Step 2. 4-Ethoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The titlecompound was prepared in a manner analogous to Intermediate 22, Step 2using the appropriate starting material substitutions. ¹H NMR (400 MHz,CDCl₃) δ 8.54 (s, 1H), 4.46 (q, J = 7.05 Hz, 2H), 3.99 (s, 2H), 3.16 (t,J = 5.93 Hz, 2H), 2.64 (t, J = 5.81 Hz, 2H), 1.42 (t, J = 7.03 Hz, 3H).[M+H] = 180.0.

Intermediate 24 4-Propoxy-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-propoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.58 (s, 1H), 5.32 (s, 1H), 4.56 (s, 2H), 4.36 (t, J= 6.66 Hz, 2H), 3.70 (t, J = 5.75 Hz, 2H), 2.70 (t, J = 5.32 Hz, 2H),1.78 - 1.87 (m, 2H), 1.61 - 1.66 (m, 2H), 1.51 (s, 9H), 1.04 (s, 3H).[M+H] = 294.3.

Step 2. 4-Propoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thismaterial was prepared using the procedure described for Intermediate 23,step 2. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 5.32 - 5.33 (m, 1H),4.35 (t, J = 6.60 Hz, 2H), 3.99 (s, 2 H), 3.16 (t, J = 5.93 Hz, 2H),2.65 (t, J = 5.81 Hz, 2H), 1.82 (sxt, J = 7.12 Hz, 2H), 1.04 (t, J =7.40 Hz, 3H). [M+H] = 194.2.

Intermediate 25 4-Isobutoxy-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-isobutoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.58 (s, 1H), 4.57 (s, 2H), 4.17 (d, J = 6.60 Hz,2H), 3.70 (t, J = 5.75 Hz, 2H), 2.72 (t, J = 5.44 Hz, 2H), 2.08 - 2.18(m, 1H), 1.51 (s, 9H), 1.04 (d, J = 6.72 Hz, 6H). [M+H] = 308.3.

Step 2. 4-Isobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The titlecompound was prepared in a manner analogous to Intermediate 23, Step 2using the appropriate starting material substitutions. ¹H NMR (400 MHz,CDCl₃) δ 8.54 (s, 1H), 5.32 (s, 1H), 4.16 (d, J = 6.60 Hz, 2H), 4.00 (s,2H), 3.18 (t, J = 5.93 Hz, 2H), 2.67 (t, J = 5.81 Hz, 2H), 2.12 (dt, J =13.36, 6.71 Hz, 1H), 1.04 (d, J = 6.72 Hz, 6H). [M+H] = 208.2.

Intermediate 264-(Cyclopropylmethoxy)-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-(cyclopropylmethoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate23, Step 1 using the appropriate starting material substitutions. [M+H]= 306.3.

Step 2.4-(Cyclopropylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.51 (s, 1H), 4.23 (d, J = 7.09 Hz, 2H), 3.97 (s,2H), 3.12 - 3.18 (m, 2H), 2.61 - 2.69 (m, 2H), 1.24 - 1.34 (m, 1H),0.57 - 0.65 (m, 2H), 0.37 (q, J = 4.89 Hz, 2H). [M+H] = 206.2.

Intermediate 274-(2-Methoxyethoxy)-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-(2-methoxyethoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate23, Step 1 using the appropriate starting material substitutions. [M+H]= 310.0.

Step 2. 4-(2-Methoxyethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.The title compound was prepared in a manner analogous to Intermediate23, Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.54 (s, 1H), 4.54 - 4.61 (m, 2H), 4.02 (s, 1H),3.98 - 4.01 (m, 2H), 3.74 - 3.82 (m, 2H), 3.45 (s, 3H), 3.26 - 3.28 (m,1H), 3.16 (t, J = 5.93 Hz, 2H), 2.68 (t, J = 5.81 Hz, 2H), 2.46 (s, 1H),2.29 (s, 1H), 2.23 (s, 1H), 2.19 (s, 1H), 1.46 (s, 1H), 1.28 (s, 1H),0.04 - 0.21 (m, 1H). [M+H] = 210.2.

Intermediate 28 4-Cyclobutoxy-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-cyclobutoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 1 using the appropriate starting material substitutions. [M+H] =306.1.

Step 2. 4-Cyclobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.51 (s, 1H), 5.25 - 5.33 (m, 1H), 3.97 (s, 2H), 3.15(t, J = 5.87 Hz, 2H), 2.63 (t, J = 5.81 Hz, 2H), 2.48 (br s, 2H), 2.10 -2.21 (m, 2H), 1.80 - 1.94 (m, 1H), 1.75 (s, 4H). [M+H] = 206.1.

Intermediate 29 4-Cyclopropoxy-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidine

Step 1. tert-Butyl4-cyclopropoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 1 using the appropriate starting material substitutions. [M+H] =292.0.

Step 2. 4-Cycloprooxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thetitle compound was prepared in a manner analogous to Intermediate 23,Step 2 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CDCl₃) δ 8.61 (s, 1H), 5.32 (s, 1H), 4.39 (tt, J = 6.22, 3.13Hz, 1H), 3.98 (s, 2H), 3.13 (t, J = 5.93 Hz, 2H), 2.56 (t, J = 5.75 Hz,2H), 0.75 - 0.89 (m, 5H). [M+H] = 192.1.

Intermediate 30. N-(2-Fluoroethyl)-2-(Piperidin-4-yl)Pyrimidin-4-AmineHydrochloride

Step 1. 2-Chloro-N-(2-fluoroethyl)pyrimidin-4-amine. 2-Fluoroethylaminehydrochloride (3.6 g, 36.5 mmol) and K₂CO₃ (13.8 g, 101 mmol) were addedto a stirred solution of 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) inACN (250 mL) and stirring was continued for 6 h. The mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (2 × 10 mL). Theorganic layer was evaporated under reduced pressure and the residue waspurified by flash chromatography to afford the title compound (3.9 g,66%) as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 - 7.88 (m,2H), 6.52 (d, J = 5.9 Hz, 1H), 4.59 (t, J = 4.9 Hz, 1H), 4.49 (t, J =4.9 Hz, 1H), 3.67 - 3.51 (m, 2H). [M+H] = 176.0.

Step 2. tert-Butyl4-(4-(2-fluoroethylamino)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate.Solutions of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(3.0 g, 9.7 mmol) in dioxane (15 mL) and sodium carbonate (5.42 g, 29mmol) in water (20 mL) were combined and degassed with argon.PdCl₂(dppf)·DCM (0.695 g, 0.85 mmol) and2-chloro-N-(2-fluoroethyl)pyrimidin-4-amine (3.5 g, 11.6 mmol) wereadded and the resulting mixture was heated to 90° C. for 4 h. Thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (2 × 20 mL). The organic layer was concentrated under reducedpressure and the residue was purified by flash chromatography to affordthe title compound (1.8 g, 58%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (d, J = 9.6 Hz, 1H), 7.05 - 6.99 (m 1H), 6.22 (d, J = 9.6Hz 1H), 5.02 (br s, 1H), 4.69 - 4.65 (dd, J = 9.6, 4.8 Hz), 4.54 - 4.57(dd, J = 9.6, 4.8 Hz), 4.41 (t, J = 7.2 Hz, 2H), 3.68 - 3.81 (m, 2H),3.68 (br s, 2H), 2.66 (m, 2H), 1.48 (s, 9H). [M+H] = 323.1.

Step 3. tert-Butyl4-(4-(2-fluoroethylamino)pyrimidin-2-yl)piperidine-1-carboxylate. Astirred suspension of tert-butyl4-(4-(2-fluoroethylamino)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.8 g, 5.6 mmol) and 10% palladium on carbon (700 mg) in ethanol (20mL) was stirred for 4 h under hydrogen. The reaction mixture wasfiltered through Celite® and the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography to afford thetitle compound (1.3 g, 72%) as a pale yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (d, J = 5.9 Hz, 1H), 7.05 (s, 1H), 6.22 (d, J = 5.9 Hz,1H), 5.02 (d, J = 17.6 Hz, 1H), 4.68 (t, J = 4.8 Hz, 1H), 4.55 (q, J =4.4, 3.9 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.77 (dd, J = 27.1, 5.2 Hz, 2H),3.60 (s, 2H), 2.66 (s, 2H), 1.48 (s, 9H), 1.25 (d, J = 4.6 Hz, 4H).[M+H] = 325.1.

Step 4. N-(2-Fluoroethyl)-2-(piperidin-4-yl)pyrimidin-4-aminehydrochloride. The title compound was prepared by treatment oftert-Butyl4-(4-(2-fluoroethylamino)pyrimidin-2-yl)piperidine-1-carboxylate withHCl, in a manner analogous to Intermediate 12, step 2. ¹H NMR (400 MHz,CDCl₃) δ 14.76 (s, 1H), 9.89 (d, J = 7.5 Hz, 1H), 9.37 - 9.09 (m, 2H),8.13 (d, J = 7.1 Hz, 1H), 6.81 (d, J = 7.0 Hz, 1H), 4.69 (t, J = 4.9 Hz,1H), 4.58 (t, J = 4.9 Hz, 1H), 3.80 (dq, J = 27.5, 5.2 Hz, 2H), 3.35 (d,J = 12.9 Hz, 2H), 3.22 (ddt, J = 11.1, 8.0, 3.9 Hz, 1H), 3.05 -2.90 (m,2H), 2.16 - 1.97 (m, 4H).

Intermediate 31.2-Isopropyl-4-methoxy-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineTrifluoroacetate

Step 1. tert-Butyl2-isopropyl-4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.2-Methylpropanimidamide hydrochloride (153 mg, 1.24 mmol) and sodiumethoxide (21% w/w, 0.62 mL, 1.66 mmol) were added to a stirred solutionof 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (225 mg,0.83 mmol) in ethanol (8.3 mL) and the reaction was refluxed for 20 h.The reaction was cooled to room temperature, diluted with DCM and washedwith brine. The aqueous layer was extracted with DCM and the combinedorganics were washed with brine, dried over MgSO₄ and concentrated undervacuum. The residue was purified by column chromatography (elution with0-100% ethyl acetate and heptane) to afford the title compound (189 mg,78%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 4.34 (s, 2H), 3.68 -3.54 (m, 2H), 2.84 (spt, J = 6.9 Hz, 1H), 2.51 (t, J = 5.7 Hz, 2H), 1.49(s, 9H), 1.28 (d, J = 7.0 Hz, 6H). [M+H] = 294.3.

Step 2. tert-Butyl4-chloro-2-isopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.A mixture of tert-Butyl2-isopropyl-4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(180 mg, 0.61 mmol) and triphenylphosphine (320 mg, 1.23 mmol) in1,2-dichloroethane (7.2 mL) was stirred for 15 min. Carbon tetrachloride(0.18 mL) was added and the reaction mixture was heated at 70° C. for 3h. The solvents were removed in vacuo and the residue was purified bycolumn chromatography (elution with 0-25% ethyl acetate and heptane) toafford the title compound (125 mg, 65%) as a colorless oil. [M+H] =312.3.

Step 3. tert-Butyl2-isopropyl-4-methoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.tert-Butyl4-chloro-2-isopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(125 mg, 0.38 mmol) was dissolved in methanol (2.35 mL) and sodiummethoxide (25% w/w, 0.34 mL, 1.51 mmol) was added. The mixture washeated to 70° C. for an hour, cooled and the solvent was evaporated. Theresidue was extracted with ethyl acetate and washed with saturatedammonium chloride. The organics were dried (MgSO₄) and the solvent wasevaporated to afford the title compound (116 mg, 96%) as a colorlessoil. [M+H] = 308.4.

Step 4. 2-Isopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinetrifluoroacetate. tert-Butyl2-isopropyl-4-methoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate(111 mg, 0.22 mmol) was dissolved in DCM (1.3 mL) and TFA (0.67 mL) wasadded. The reaction mixture was stirred for one hour and concentratedunder vacuum to afford the title compound (70 mg, 89%) as a yellow oil.[M+H] = 208.2.

Intermediate 32.2-Cyclopropyl-4-Methoxy-5,6,7,8-Tetrahydropyrido[3,4-d]PyrimidineTrifluoroacetate

Step 1. tert-Butyl2-cyclopropyl-4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate31, Step 1 using the appropriate starting material substitutions. ¹H NMR(400 MHz, CD₃OD) δ 4.24 (s, 2H), 3.66 - 3.54 (m, 2H), 2.49 (t, J = 5.8Hz, 2H), 1.90 - 1.80 (m, 1H), 1.48 (s, 9H), 1.16 - 1.01 (m, 4H). [M+H] =292.3.

Step 2. tert-Butyl4-chloro-2-cyclopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate31, Step 2 using the appropriate starting material substitutions. [M+H]= 310.3.

Step 3. tert-Butyl2-cyclopropyl-4-methoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate.The title compound was prepared in a manner analogous to Intermediate31, Step 3 using the appropriate starting material substitutions. [M+H]= 306.3.

Step 4.2-Cyclopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinetrifluoroacetate. The title compound was prepared in a manner analogousto Intermediate 31, Step 4 using the appropriate starting materialsubstitutions. [M+H] = 206.3.

Intermediate 33 N-((6-Methoxypyrimidin-4-yl)Methyl)Cyclopropanamine

Cyclopropanamine (0.048 mL, 0.69 mmol) was added to a mixture of4-(chloromethyl)-6-methoxypyrimidine (100 mg, 0.63 mmol) and potassiumcarbonate (131 mg, 0.95 mmol) in DMF (3.2 mL) and the mixture was heatedat 40° C. for 15 h. The reaction was filtered and the solvent wasremoved under vacuum to afford a mixture of the title product andN,N-bis((6-methoxypyrimidin-4-yl)methyl)cyclopropanamine (113 mg). [M+H]was not observed.

Intermediate 34 A-((6-Methoxypyrimidin-4-yl)Methyl)Ethanamine

The title compound was prepared in a manner analogous to Intermediate33, using the appropriate starting material substitutions. [M+H] =168.1.

Intermediate 353-Cyclopropyl-1-Ethyl-5,6,7,8-Tetrahydroimidazo[1,5-a]Pyrazine

Step 1. tert-Butyl3-Cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. To astirred solution of3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (7.0 g, 43 mmol)and DIEA (145 mL, 86 mmol) in 1,2-dichloroethane (70 mL) was addeddi-tert-butyl dicarbonate (12.2 g, 55.8 mmol) in portions. The mixturewas stirred for 5 h, and then it was diluted with DCM, washed with waterand brine, dried (MgSO₄) and concentrated to provide an oily residue.This material was purified by flash chromatography (elution with 10-100%ethyl acetate in heptane) to provide the title compound (4.13 g, 37%).¹H NMR (400 MHz, CDCl₃) δ 6.68 (s, 1H), 4.62 (s, 2H), 3.98 - 4.06 (m,2H), 3.83 (t, J = 5.44 Hz, 2H), 1.69 - 1.81 (m, 1H), 1.51 (s, 9H),0.97 - 1.03 (m, 2H), 0.90 - 0.97 (m, 2H). [M+H] = 264.3.

Step 2. tert-Butyl3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-α]pyrazine-7(8H)-carboxylate.tert-Butyl3-Cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (1.12g, 4.25 mmol) and 1-iodopyrrolidine-2,5-dione (1.15 g, 5.10 mmol) werecombined and diluted with ACN (11.2 mL). The mixture was stirred for 22h and then it was diluted with ethyl acetate and washed sequentiallywith a 1 M aqueous solution of Na₂SOs and a 1 M aqueous solution ofNa₂CO₃, then dried (MgSO₄) and concentrated. The residue was purified byflash chromatography (elution with 10-50% ethyl acetate in heptane) toafford the title compound (1.16 g, 71%) as a gum. ¹H NMR (400 MHz,CDCl₃) 6 4.46 (s, 2H), 3.95 - 4.05 (m, 2H), 3.82 (t, J = 5.32 Hz, 2H),1.68 - 1.78 (m, 1H), 1.53 (s, 9H), 1.01 - 1.07 (m, 2H), 0.91 - 1.00 (m,2H). [M+H] = 390.2.

Step 3. tert-Butyl3-cyclopropyl-l-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate.A mixture of tert-butyl3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate(277 mg, 0.71 mmol),(R)-l-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphinepalladium(II) dichloride (26 mg, 0.04 mmol), potassiumfluoride/potassium vinyltrifluoroborate (1:1) (286 mg, 2.13 mmol), ACN(3.6 mL) and aqueous sodium bicarbonate (1 M, 1.8 mL, 1.8 mmol) werecombined in a 20 mL vial and degassed with nitrogen for 1 min. Themixture was heated to 90° C. for 8 h. Some starting material persistedso additional potassium fluoride/potassium vinyltrifluoroborate (1:1)(286 mg, 2.13 mmol), palladium catalyst (26 mg, 0.04 mmol), ACN (3.6 mL)and sodium bicarbonate (1 M, 1.8 mL, 1.8 mmol) were added, the mixturewas again degassed and heated at 90° C. for 16 h. The mixture was shakenwith ethyl acetate and an aqueous solution of Na₂CO₃, and the resultingaqueous layer was extracted with ethyl acetate. The combined organicswere dried (MgSO₄) and concentrated, and the residue was purified byflash chromatography (elution with 10-75% ethyl acetate in heptane) toprovide the title compound (76 mg, 37%). ¹H NMR (400 MHz, CDCl₃) δ 6.55(dd, J = 11.1, 17.5 Hz, 1H), 5.56 (dd, J = 1.5, 17.6 Hz, 1H), 5.12 (dd,J = 1.3, 11.1 Hz, 1H), 4.66 (s, 2H), 4.07 - 3.95 (m, 2H), 3.83 (t, J =5.3 Hz, 2H), 1.73 (tt, J = 5.2, 8.2 Hz, 1H), 1.52 (s, 9H), 1.07 - 0.99(m, 2H), 0.98 - 0.88 (m, 2H). [M+H] = 290.3.

Step 4. tert-Butyl3-cyclopropyl-l-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate.A mixture of tert-Butyl3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate(73 mg, 0.25 mmol), and palladium on activated carbon (27 mg, 0.03 mmol)in ethyl acetate (1.5 mL) was stirred under 180 psi of hydrogen for 16h. The mixture was filtered through Celite® and concentrated undervacuum to provide the title compound (90 mg, 100%). ¹H NMR (400 MHz,CDCl₃) b 4.55 (s, 2H), 3.98 (t, J = 6.1 Hz, 2H), 3.81 (t, J = 5.4 Hz,2H), 2.48 (q, J = 7.6 Hz, 2H), 1.75 - 1.66 (m, 1H), 1.51 (s, 9H), 1.18(t, J = 7.6 Hz, 3H), 1.01 -0.95 (m, 2H), 0.95 - 0.89 (m, 2H). [M+H] =292.3.

Step 5. 3-Cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-α]pyrazine.tert-Butyl3-cyclopropyl-l-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate(90 mg, 0.31 mmol) was stirred in 2-methyltetrahydrofuran (0.45 mL) andTFA (0.45 mL) for 3 h. The solvent was evaporated and the residuediluted with 1 M Na₂CO₃. The solution was extracted with a 5:1 solutionof DCM-methanol (3 × 25 mL) and the combined extracts were dried (MgSO₄)and concentrated to provide the title compound (54 mg, 91%) as a lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.99 (s, 2H), 3.93 (t, J = 5.6Hz, 2H), 3.23 (t, J = 5.6 Hz, 2H), 2.51 - 2.43 (m, 2H), 1.72 (tt, J =5.1, 8.2 Hz, 1H), 1.16 (t, J = 7.6 Hz, 3H), 1.03 - 0.98 (m, 2H), 0.94 -0.87 (m, 2H). [M+H] = 192.2.

Example 1.(6-Methyl-4-((1-Methylcyclopropyl)amino)Furo[2,3-d]Pyrimidin-5-yl)(4-Phenylpiperazin-1-yl)Methanone(or6-Methyl-N-(1-Methylcyclopropyl)-5-(4-Phenylpiperazine-1-Carbonyl)Furo[2,3-d]Pyrimidin-4-Amine)

Step 1.(4-Chloro-6-methylfuro[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone.4-Chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic acid (Intermediate2, 500 mg, 1.65 mmol) and DIEA (0.57 ml, 3.3 mmol) were combined in DMA(8.2 mL) and treated with HATU (810 mg, 2.14 mmol) and1-phenylpiperazine (0.26 mL, 1.73 mmol). The mixture was stirred for 1h, diluted with water and extracted with ethyl acetate (2 × 50 mL). Thecombined organic layers were washed with brine and dried over MgSO₄. Thesolvent was evaporated and the residue was purified by columnchromatography (elution with 0-80% ethyl acetate in heptane) to affordthe title compound (320 mg, 54%) as a white solid. [M+H] = 357.0.

Step 2.(6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone.(4-Chloro-6-methylfuro[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone(25 mg, 0.07 mmol) was dissolved in DMA (0.70 mL) and was treated withDIEA (0.050 mL, 0.28 mmol) and 1-methylcyclopropanamine hydrochloride(0.01 g, 0.09 mmol). The mixture was stirred at 85° C. for 16 h andcooled. It was filtered and purified by preparative HPLC (elution with20-80% ACN with 0.05% TFA). Fractions containing product were combinedand lyophilized to afford the title compound (26 mg, 74%) as a whitepowder. ¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.33 - 7.26 (m, 2H),7.04 (d, J = 7.8 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 4.09 - 3.74 (m, 4H),3.30 - 3.16 (m, 4H), 2.62 - 2.56 (m, 3H), 1.58 -1.49 (m, 3H), 1.00 -0.82 (m, 4H). [M+H] = 392.3.

Example 2.(2-Cyclopropyl-7,8-Dihydropyrido[4,3-d]Pyrimidin-6(5H)-yl)(6-Methyl-4-((1-Methylcyclopropyl)Amino)Furor[2,3-d]Pyrimidin-5-yl)Methanone(or 5-{2-Cyclopropyl-5H,6H,7 H,8H-Pyridor 4,3-Dlpyrimidine-6-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine)

DIEA (0.063 mL, 0.36 mmol) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1, 25 mg, 0.09 mmol) were combined in DMA (0.91 ml).HATU (52 mg, 0.14 mmol) and2-cyclopropyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride(25 mg, 0.12 mmol) were added and the mixture was stirred for 30minutes. The mixture was filtered and purified by preparative HPLC(elution with 10-70% ACN with 0.05% TFA). Fractions containing productwere combined and lyophilized to afford the title compound (33 mg, 70%)as a white powder. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J = 5.6 Hz, 1H),8.35 (s, 1H), 8.27 (dt, J = 1.6, 7.9 Hz, 1H), 7.68 (dt, J = 1.1, 6.7 Hz,1H), 7.61 (d, J = 8.2 Hz, 1H), 4.65 - 3.49 (m, 4H), 2.57 (s, 3H), 2.43(br s, 2H), 2.11 (t, J = 3.4 Hz, 1H), 1.51 (s, 3H), 0.94 - 0.79 (m, 4H).[M+H] = 390.3.

Example 3.N-(1-(Fluoromethyl)Cyclopropyl)-6-Methyl-4-((1-Methylcyclopropyl)Amino)Furor2,3-D1pyrimidine-5-Carboxamide

6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1, 1.00 g, 4.04 mmol) and1-(fluoromethyl)cyclopropanamine hydrochloride (0.63 g, 5.06 mmol) weretaken up in DMA (5 mL). DIEA (2.12 mL, 12.1 mmol) was added, followed by2-chloro-1-methylpyridin-1-ium iodide (1.34 g, 5.26 mmol). After 7 h ofstirring, the reaction was judged to be complete and water (5 mL) wasadded. The reaction was stirred for 16 h during which time a solidformed. The slurry was further diluted with water (2 mL) and the solidwas collected and rinsed with heptane to afford the title compound (1.09g, 85%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (br s, 1H),8.46 (s, 1H), 6.39 (br s, 1H), 4.52 (d, J = 48 Hz, 2H), 2.68 (s, 3H),1.55 (s, 3H), 1.10 (s, 4H), 0.92 - 0.76 (m, 4H). [M+H] = 319.3.

Example 4.(4-Methoxy-5,8-Dihydropyridor[3,4-d]Pyrimidin-7(6H)-yl)(6-Methyl-4-((1-Methylcyclopropyl)amino)furo[2,3-d]Pyrimidin-5-yl)Methanone(or5-{4-Methoxy-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine)

6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1, 3.80 g, 15.4 mmol),4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (4.08g, 19.2 mmol) and HATU (8.77 g, 23.05 mmol) were combined and DMA (38mL) was added. The slurry was cooled in an ice bath. DIEA (10.7 mL,61.48 mmol) was added slowly, maintaining the internal temperature below15° C. The reaction was judged to be complete after 1 h. The reactionwas quenched with sodium hydroxide (0.1 N, 40 mL, 4.0 mmol) and thendiluted with water (40 mL). The solution was stirred at ambienttemperature overnight, during which time a solid formed. The solid wascollected and rinsed with water to afford the title compound (4.45 g,73%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.33(s, 1H), 7.12 (br s, 1H), 4.68 (br s, 2H), 3.95 (s, 3H), 3.78 (d, J=11.7Hz, 2H), 2.69 (br s, 2H), 2.47 (s, 3H), 1.38 (s, 3H), 0.70 - 0.57 (m,4H). [M+H] = 395.5.

Example 5.(4-Fluoro-5,8-Dihydropyridor[3,4-d]Pyrimidin-7(6H)-yl)(6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo[2,3-d]Pyrimidin-5-yl)Methanone(or5-{4-Fluoro-5H,6H,7H,8H-Pyridor[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropylfuro[2,3-d]Pyrimidin-4-Amine)

4-Fluoro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride wascoupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 8.72 (s,1H), 8.44 (s, 1H), 4.93 (br s, 2H), 4.16 - 3.89 (m, 2H), 3.00 - 2.91 (m,2H), 2.64 - 2.57 (m, 3H), 1.53 - 1.46 (m, 3H), 0.97 - 0.88 (m, 4H).[M+H] = 383.0.

Example 6.5-{4-Chloro-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride wascoupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) 5 8.79 (s,1H), 8.42 (s, 1H), 4.90 (br s, 2H), 4.02 (br s, 2H), 3.04 - 2.98 (m,2H), 2.60 (s, 3H), 1.48 (s, 3H), 0.94 - 0.85 (m, 4H). [M+H] = 398.93.

Example 7,5-{4-[2-Fluoroethyl)Amino]-5H,6H,7H,8H,-Pyridor[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropylfuro[2,3-d]Pyrimidin-4-AmineTrifluoroacetate

To a stirred solution of5-{4-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine(Example 6, 40 mg, 0.08 mmol) in ACN (0.78 mL) was added TEA (0.038 mL,0.27 mmol) and 2-fluoroethanamine hydrochloride (12 mg, 0.12 mmol) andthe mixture was heated at 60° C. for 20 h, then 80° C. for 3 h.Potassium carbonate (11 mg, 0.08 mmol) was added and heating at 80° C.was continued for 20 h. The mixture was cooled, diluted with methanol,filtered and purified by preparative HPLC (elution with 3-45% ACN inwater containing 0.05% TFA). Fractions containing product were combinedand lyophilized to afford the title compound (12 mg, 42%) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.37 (s, 1H), 4.92 - 4.87(m, 2H), 4.77 - 4.55 (m, 2H), 4.18 -3.82 (m, 4H), 2.78 - 2.65 (m, 2H),2.59 (s, 3H), 1.48 (s, 3H), 0.88 - 0.76 (m, 4H). [M+H] = 426.0.

Example 8.A-((5-Chloropyrazin-2-yl)Methyl)-6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo[2,3-d]Pyrimidine-5-Carboxamide

Chloropyrazin-2-yl)methanamine hydrochloride was coupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) 5 8.64 (d, J= 1.5 Hz, 1H), 8.51 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 4.76 (s, 2H),2.75 (s, 3H), 1.50 (s, 3H), 0.96 - 0.85 (m, 4H). [M+H] = 372.93.

Example 9.N-((5-Fluoropyrazin-2-yl)Methyl)-6-Methyl-4-((1-Methylcyclopropyl)Amino)furor2,3-D1pyrimidine-5-Carboxamide

A mixture ofN-((5-chloropyrazin-2-yl)methyl)-6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxamide(Example 8, 13 mg, 0.03 mmol) and potassium fluoride (16 mg, 0.27 mmol)in DMSO (0.89 mL) was heated at 100° C. for 20 h. The mixture wastransferred to a microwave vial, ACN (1 mL) was added and the reactionmixture was heated by microwave at 110° C. for 15 min, 130° C. for 30min, 150° C. for 1h, 160° C. for 1 h and finally 170° C. for 1 h. Themixture was diluted with methanol, filtered and purified by prep HPLC(elution with 5-50% ACN in water containing 0.05% TFA). Fractionscontaining product were combined and lyophilized to afford the titlecompound (3.0 mg, 19%) as an orange solid. ¹H NMR (400 MHz, CD₃OD) δ8.49 (dd, J = 1.2, 8.2 Hz, 1H), 8.36 (s, 1H), 8.34 (s, 1H), 4.77 (s,2H), 2.76 - 2.74 (m, 3H), 1.50 (s, 3H), 0.94 - 0.86 (m, 4H). [M+H] =356.9.

Example 10.N-(5-Hydroxypyridin-2-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

6-(Aminomethyl)pyridin-3-ol hydrochloride was coupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 8.35 (s,1H), 8.21 (d, J = 2.3 Hz, 1H), 7.83 - 7.72 (m, 2H), 4.76 (s, 2H), 2.75(s, 3H), 1.48 (s, 3H), 0.89 - 0.84 (m, 4H).

Example 11.N-((5-(Fluoromethoxy)Pyridin-2-yl)Methyl)-6-Methyl-4-((1-Methylcyclopropyl)Amino)Furor2,3-D1pyrimidine-5-Carboxamide

To a solution ofN-[(5-hydroxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide(Example 10, 100 mg, 0.16 mmol) in DMF (1.1 mL) was added cesiumcarbonate (107 mg, 0.33 mmol) and a solution of fluoromethyl4-methylbenzene-1-sulfonate (67 mg, 0.33 mmol) in DMF (0.55 mL). After 1h stirring at room temperature, the reaction mixture was heated at 70°C. for 45 min. The reaction was cooled, diluted with methanol, filteredand purified by prep HPLC (elution with 5-50% ACN in water containing0.05% TFA). Fractions containing product were combined and lyophilizedto afford the title compound (3.0 mg, 19%) as an orange solid. ¹H NMR(400 MHz, CD₃OD) δ 8.39 (d, J = 2.8 Hz, 1H), 8.37 (s, 1H), 7.68 - 7.58(m, 1H), 7.49 (d, J = 8.7 Hz, 1H), 5.95 - 5.72 (m, 2H), 4.71 (s, 2H),2.76 (s, 3H), 1.51 (s, 3H), 0.96 - 0.84 (m, 4H). [M+H] = 386.0.

Example 12,3-Fluoro-5-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)pyridine-2-carbonitrile.

3-Fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-2-carbonitrile(Intermediate 4) was coupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 8.73 (t, J= 1.5 Hz, 1H), 8.33 (s, 1H), 7.96 (dd, J = 1.7, 10.4 Hz, 1H), 6.58 (brs, 1H), 4.44 (br s, 2H), 4.14-3.74 (m, 2H), 2.73 (br s, 2H), 2.55 (s,3H), 1.49 (s, 3H), 0.86-0.73 (m, 4H). [M+H] = 433.0.

Example 13. 5 - F4-(5 -Fluoro-6-Methoxypyridin-3-yl)-1,2,3,6-Tetrahydropyridine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

5-Fluoro-6-methoxy-1′,2′,3′,6′-tetrahydro-3,4′-bipyridinetrifluoroacetate (Intermediate 5) was coupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) 5 8.31 (s,1H), 8.02 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 2.1, 11.9 Hz, 1H), 6.18 (brs, 1H), 4.34 (br s, 2H), 4.01 (s, 4H), 2.67 (br s, 2H), 2.53 (s, 3H),1.48 (s, 3H), 0.88 - 0.68 (m, 4H). [M+H] = 438.0.

Example 14. 5 - [4-(5-Fluoro-6-Methoxypyridin-3-yl)Piperidine-1-Carbonyl-6-Methyl-Af-(1-Methylcyclopropyl)furo[2,3-d]Pyrimidin-4-Amine

A mixture of5-[4-(5-fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine(Example 13, 85 mg, 0.19 mmol) and palladium on activated carbon (50 mg,0.05 mmol) in ethanol (5 mL) were stirred under 1 atm of hydrogen for 1h. The mixture was filtered through a pad of Celite®, concentrated, andthe residue was purified by flash LC (elution with 30-100% ethyl acetatein heptane) to afford the title compound (21 mg, 25%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.85 (s, 1H), 7.44 (d, J = 10.0Hz, 1H), 3.98 (s, 3H), 3.61 - 3.02 (m, 4H), 2.94 (br s, 1H), 2.54 (s,3H), 2.09 - 1.86 (m, 2H), 1.70 (d, J = 14.1 Hz, 2H), 1.52 (s, 3H), 0.92-0.72 (m, 4H). [M+H] = 440.0.

Example 15.5-[4-(5-Fluoropyrimidin-2-yl)-1,2,3,6-Tetrahydropyridine-1-Carbonyll-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine.

Step 1.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine.The title compound was synthesized in a manner analogous to Example 2,using6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) and4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine asthe starting materials. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (br s, 1H), 6.97(br s, 1H), 6.49 (br s, 1H), 4.48 - 3.95 (m, 2H), 3.61 (br s, 2H), 2.45(br s, 3H), 2.37 (br s, 2H), 2.04 (br s, 1H), 1.50 (br s, 3H), 1.36 -1.17 (m, 14H), 0.96 - 0.59 (m, 4H). [M+H] = 439.0.

Step 2.5-[4-(5-Fluoropyrimidin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine(64 mg, 0.15 mmol) and 2-bromo-5-fluoropyrimidine (31 mg, 0.18 mmol)were combined and dissolved in dioxane (0.8 mL) and ethyl alcohol (0.3mL) with nitrogen bubbling through the mixture. Water (0.2 mL), aqueoussodium carbonate (2 M, 0.22 mL, 0.44 mmol) andtetrakis(triphenylphosphine)palladium(0) (8 mg, 0.01 mmol) were addedand the mixture was heated at 120° C. for 15 min in a microwave reactor.The mixture was filtered and purified by preparative HPLC (elution with15-75% ACN in water containing 0.05% TFA). Fractions containing productwere poured into ethyl acetate (20 mL), washed with saturated sodiumbicarbonate (20 mL), dried (MgSO₄) and concentrated. The residue waspurified by flash LC (30-100% ethyl acetate in heptane) to afford thetitle compound (5.0 mg, 8%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.81 (d, J = 1.5 Hz, 2H), 8.32 (s, 1H), 6.36 (br s, 1H), 4.39 (br s,2H), 3.93 (br s, 2H), 2.72 (br s, 2H), 2.55 (s, 3H), 1.49 (s, 3H),0.86 - 0.66 (m, 4H). [M+H] = 409.0.

Example 16 and 17.3-(Fluoromethyl)-7-(6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]7]Pyrimidine-5-Carbonyl}-3H,4H,5H,6H,7H,8H,-Pyrido[3,4-d]Pyrimidin-4-Oneand5-[4-(Fluoromethoxy)-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-7-Carbonyl]-6-Methyl-A-(1-Methylcyclopropyl)Furo[2,3-d7]Pyrimidin-4-Amine

Step 1.7-(6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one.5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled, in a manner analogous to Example 2,to afford the title compound as a solid. ¹H NMR (400 MHz, CD₃OD) δ 8.46(s, 1H), 8.30 - 8.21 (m, 1H), 4.72 (br s, 2H), 4.12 - 3.67 (m, 2H), 3.46(br s, 6H), 3.25 - 3.06 (m, 8H), 2.82 - 2.74 (m, 2H), 2.68 (s, 3H), 1.53(s, 4H), 1.08 (br s, 2H), 0.97 (s, 2H). [M+H] = 381.0.

Step 2.3-(Fluoromethyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H,-pyrido[3,4-d]pyrimidin-4-oneand 5-[4-(fluoromethoxy)-5H, 6H, 7H,8H,-pyrido[3,4-]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.To a solution of7-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one(38 mg, 0.06 mmol) in DMF (0.38 mL) was added cesium carbonate (38 mg,0.12 mmol) and a solution of fluoromethyl 4-methylbenzene-1-sulfonate(24 mg, 0.12 mmol) in DMF (0.19 mL). After 1 h stirring at 60° C., thereaction mixture was cooled, diluted with methanol, filtered andpurified by prep HPLC (elution with 15-50% ACN in water containing 0.05%TFA). Fractions containing the two products were lyophilized to affordExample 16 (6.2 mg, 20%) and Example 17 (8.9 mg, 29%), both as yellowsolids. Example 16: ¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.41 - 8.37(m, 1H), 6.08 - 5.90 (m, 2H), 4.65 (br s, 2H), 3.91 (br s, 2H), 2.72 (brs, 2H), 2.58 (s, 3H), 1.49 (s, 3H), 0.88 (d, J = 10.6 Hz, 4H). [M+H] =413.1. Example 17: ¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 8.41 (s, 1H),6.27 - 6.04 (m, 2H), 4.92 (br s, 2H), 4.22 - 3.82 (m, 2H), 2.90 (t, J =5.3 Hz, 2H), 2.59 (s, 3H), 1.48 (s, 3H), 0.95 - 0.83 (m, 4H). [M+H] =413.0.

Example 18.5-{4-[(3R)-3-Fluoropyrrolidin-1-yl]-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-A-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

(R)(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride (Intermediate 8) and6-methyl((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled, in a manner analogous to Example 2to afford the title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H),8.38 (s, 1H), 5.54 - 5.31 (m, 1H), 5.01 (br s, 1H), 4.74 (d, J = 16.9Hz, 1H), 4.34 - 4.16 (m, 3H), 4.16 - 3.99 (m, 2H), 3.63 (br s, 1H), 3.27(br s, 1H), 3.22 - 3.10 (m, 1H), 2.61 (s, 3H), 2.52 - 2.34 (m, 1H),2.34 - 2.07 (m, 1H), 1.50 (s, 3H), 0.95 - 0.77 (m, 4H). [M+H] = 452.0.

Example 19.7-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}-5,6,7,8-Tetrahydro-1,7-Naphthyridin-4-Ol

5,6,7,8-Tetrahydro-1,7-naphthyridin-4-ol hydrochloride was coupled to6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1), in a manner analogous to Example 2, to afford thetitle compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 8.40 - 8.29(m, 2H), 7.07 (d, J = 6.8 Hz, 1H), 5.02 (br s, 2H), 3.97 (br s, 2H),2.90 (br s, 2H), 2.58 (s, 3H), 1.46 (s, 3H), 0.86 - 0.75 (m, 4H). [M+H]= 379.98.

Example 20.5-[4-(2-Fluoroethoxy)-5,6,7,8-Tetrahydro-1,7-Naphthyridine-7-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo2,3-d]Pyrimidin-4-AmineTrifluoroacetate

To a stirred solution of7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-5,6,7,8-tetrahydro-1,7-naphthyridin-4-ol(Example 19, 20 mg, 0.04 mmol) in DMF (0.83 mL) was added cesiumcarbonate (27 mg, 0.08 mmol) and a solution of 2-fluoroethyl4-methylbenzene-1-sulfonate (12 mg, 0.05 mmol) in DMF (0.2 mL). Thereaction mixture was heated at 60° C. for 20 h, then the mixture wascooled, diluted with methanol, filtered and purified by prep HPLC(elution with 5-45% ACN in water containing 0.05% TFA). Fractionscontaining product were combined and lyophilized to afford the titlecompound (8.3 mg, 37%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.62(d, J = 6.7 Hz, 1H), 8.40 (s, 1H), 7.51 (d, J = 7.0 Hz, 1H), 5.11 (br s,2H), 4.94 - 4.89 (m, 1H), 4.82 - 4.77 (m, 1H), 4.73 -4.67 (m, 1H),4.65 - 4.60 (m, 1H), 4.00 (br s, 2H), 2.99 (t, J = 5.6 Hz, 2H), 2.61 (s,3H), 1.47 (s, 3H), 0.92 - 0.79 (m, 4H). [M+H] = 426.1.

Example 21.5[3-(2-Fluoropyridin-4-yl)Pyrrolidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)furo[2,3-d]Pyrimidin-4-Amine

2-Fluoro-4-(pyrrolidin-3-yl)pyridine (Intermediate 12) and6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled, in a manner analogous to Example 2,to provide the title compound. ¹H NMR (400 MHz, CD₃OD) 5 8.57 (s, 1H),8.31 (s, 1H), 4.79 (br s, 2H), 4.19 - 3.79 (m, 5H), 2.82 (br s, 2H),2.53 (s, 3H), 1.46 (s, 3H), 0.81 - 0.68 (m, 4H). [M+H] = 396.1.

Example 22.2-Isopropyl-7-(6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo2,3-d]1PYRIMIDINE-5-Carbonyl)-5,6,7,8-Tetrahydropyridor[3,4-d]Pyrimidin-4(3H)-One(or7-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}-2-(Propan-2-yl)-3H,4H,5H,6H,7H,8H-pyridor[3,4-d]Pyrimidin-4-One)

Step 1. Ethyl1-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-3-oxopiperidine-4-carboxylate.Ethyl 3-oxopiperidine-4-carboxylate and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2 toafford the title compound as a solid. [M+H] = 401.1.

Step 2.2-Isopropyl-7-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one.To a stirred solution of isobutyrimidamide hydrochloride (92 mg, 0.75mmol) and1-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-3-oxopiperidine-4-carboxylate(200 mg, 0.50 mmol) in ethanol (5 mL) was added sodium ethoxide inethanol (21% w/w, 0.37 mL, 1.0 mmol). The mixture was heated to refluxfor 2 h, cooled to room temperature, diluted with DCM and washed withwater. The aqueous layer was extracted with DCM and the combinedorganics were washed with brine, dried over MgSO₄ and concentrated undervacuum. The solvent was evaporated and the residue was dissolved inmethanol and purified by prep HPLC (elution with 5-50% ACN in watercontaining 0.05% TFA). The fraction containing product was lyophilizedto afford the title compound (19 mg, 7%) as an off-white solid. ¹H NMR(400 MHz, CD₃OD) δ 8.42 (s, 1H), 4.63 (br s, 2H), 3.91 (br s, 2H), 2.87(td, J = 6.8, 13.6 Hz, 1H), 2.67 (br s, 2H), 2.60 (s, 3H), 1.50 (s, 3H),1.29 (d, J = 6.8 Hz, 6H), 0.93 - 0.86 (m, 4H). [M+H] = 423.0.

Example 23.5-{4-Ethyl-5H,6H,7H,8H-Pyridor[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

4-Ethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride(Intermediate 18) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2 toprovide the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.49(s, 1H), 7.09 (br s, 1H), 4.82 (br s, 2H), 3.70 - 4.29 (m, 2H), 2.95 (t,J = 5.62 Hz, 2H), 2.81 (q, J = 7.50 Hz, 2H), 2.53 (s, 3H), 1.50 (s, 3H),1.34 (t, J = 7.52 Hz, 3H), 0.75 - 0.81 (m, 4H). [M+H] = 393.4.

Example 24.7-(6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo[2,3-d]Pyrimidine-5-Carbonyl)-5,6,7,8-Tetrahydropyridor[3,4-d]Pyrimidine-4-Carbonitrile(or7-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-4-Carbonitrile)

5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile (Intermediate22) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H),8.50 (s, 1H), 7.00 (br s, 1H), 4.95 (br s, 2H), 3.76-4.48 (m, 2H), 3.21(t, J = 5.75 Hz, 2H), 2.56 (s, 3H), 1.52 (s, 3H), 0.80 (d, J = 8.07 Hz,4H). [M+H] = 390.4.

Example 25.5-{4-Ethoxy-5H,6H,7H,8H-Pyrido[3,4-d]Pyrimidine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

4-Ethoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Intermediate 23) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H),8.48 (s, 1H), 7.00 (br s, 1H), 4.75 (br s, 2H), 4.50 (q, J = 7.09 Hz,2H), 3.56 - 4.23 (m, 2H), 2.83 (t, J = 5.62 Hz, 2H), 2.52 (s, 3H), 1.51(s, 3H), 1.44 (t, J = 7.09 Hz, 3H), 0.71 - 0.83 (m, 4H). [M+H] = 409.4.

Example 26.(4-(4-((2-Fluoroethyl)Amino)Pyrimidin-2-yl)Piperidin-1-yl)(6-Methyl-4-((1-Methylcyclopropyl)Amino)Furo[2,3-d]Pyrimidin-5-yl)Methanone(orN-(2-Fluoroethyl)-2-(1-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}Piperidin-4-yl)Pyrimidin-4-Amine)

N-Fluoroethyl)-2-(piperidin-4-yl)pyrimidin-4-amine hydrochloride(Intermediate 30) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. [M+H] = 454.3.

Example 27.5-[4-Methoxy-2-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-Af-(l-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

2-Isopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinetrifluoroacetate (Intermediate 31) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H),4.80 (br s, 2H), 4.23 - 3.77 (m, 5H), 3.10 - 2.99 (m, 1H), 2.79 (t, J =5.6 Hz, 2H), 2.57 (s, 3H), 1.46 (s, 3H), 1.32 (d, J = 6.7 Hz, 6H), 0.83(d, J = 4.3 Hz, 4H). [M+H] = 437.5.

Example 28.N-Cyclopropyl-/V-[(6-Methoxypyrimidin-4-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]furo[2,3-d]Pyrimidine-5-Carboxamide

N-(Methoxypyrimidin-4-yl)methyl)cyclopropanamine (Intermediate 33) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.81 (br s, 1H),8.33 (s, 1H), 7.83 - 7.58 (m, 1H), 6.87 (s, 1H), 5.02 - 4.89 (m, 1H),4.82 - 4.68 (m, 1H), 4.03 (s, 3H), 2.96 (br s, 1H), 2.55 (s, 3H), 1.56(s, 3H), 0.83 (br s, 4H), 0.68 (br s, 4H). [M+H] = 409.4.

Example 29.5-(3-Cyclopropyl-1-ethyl-5H,6H,7H,8H-Imidazor[,5-α]Pyrazine-7-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

3-Cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(Intermediate 35) and6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylicacid (Intermediate 1) were coupled in a manner analogous to Example 2,to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H),6.97 (br s, 1H), 4.77 (br s, 2H), 4.12 (br s, 4H), 2.51 (s, 3H), 2.46(q, J = 7.4 Hz, 2H), 1.80 - 1.70 (m, 1H), 1.53 (s, 3H), 1.16 (t, J = 7.6Hz, 3H), 1.02 (td, J = 2.7, 5.1 Hz, 2H), 0.99 - 0.94 (m, 2H), 0.86 -0.81 (m, 2H), 0.78 (s, 2H). [M+H] = 421.3.

Example 30 - Example 760 were prepared in a manner analogous to Example2, with the appropriate starting material substitutions.

Example 30.6-Methyl-N-(1-Methylcyclopropyl)-5-[(1R,5S,6S)-6-(Pyridin-2-yl)-3-Azabicyclor3.1.01Hexane- 3-Carbony 11 Furor2,3-D]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J = 5.6 Hz, 1H), 8.35 (s, 1H), 8.27(dt, J = 1.6, 7.9 Hz, 1H), 7.68 (dt, J = 1.1, 6.7 Hz, 1H), 7.61 (d, J =8.2 Hz, 1H), 4.65 - 3.49 (m, 4H), 2.57 (s, 3H), 2.43 (br s, 2H), 2.11(t, J = 3.4 Hz, 1H), 1.51 (s, 3H), 0.94 - 0.79 (m, 4H). [M+H] = 390.3.

Example 31.5-[3-(5-Fluoropyridin-2-yl)Azetidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 5.0 Hz,1H), 8.41 (s, 1H), 7.66 - 7.58 (m, 1H), 4.75 - 4.66 (m, 2H), 4.50 - 4.37(m, 2H), 4.37 - 4.26 (m, 1H), 2.64 (s, 3H), 1.53 (s, 3H), 1.02 - 0.85(m, 4H). [M+H] = 382.3.

Example 32.4-(1-(6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}Azetidin-3-yl)Benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.80 - 7.73 (m, 2H), 7.60 (d, J= 8.2 Hz, 2H), 4.75 - 4.63 (m, 2H), 4.32 (br s, 2H), 4.22 - 4.09 (m,1H), 2.63 (s, 3H), 1.53 (s, 3H), 1.02 -0.83 (m, 4H). [M+H] = 388.4.

Example 33.6-Methyl-N-(1-Methylcyclopropyl)-5-[3-(1,3-Thiazol-2-yl)Azetidine-1-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.43 - 8.36 (m, 1H), 7.82 (d, J = 3.4 Hz, 1H),7.57 (d, J = 3.3 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.57 - 4.34 (m, 3H), 2.64(s, 3H), 1.53 (s, 3H), 1.03 - 0.87 (m, 4H). [M+H] = 370.3.

Example 34.N-[6-(Furan-3-yl)Pyridin-3-yl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) 5 8.95 (d, J = 2.2 Hz, 1H), 8.39 (s, 1H), 8.35 -8.23 (m, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.70 (t, J = 1.7 Hz, 1H), 7.04(dd, J = 0.8, 1.9 Hz, 1H), 2.82 - 2.77 (m, 3H), 1.55 - 1.49 (m, 3H),0.95 - 0.82 (m, 4H). [M+H] = 390.3.

Example 35.6-Methyl-N-(1-Methylcyclopropyl)-5-[4-(1,3-Thiazol-2-yl)Piperazine-1-Carbonyl]furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.44 - 8.33 (m, 1H), 7.29 (d, J = 4.0 Hz, 1H),6.95 (d, J = 4.0 Hz, 1H), 3.90 (br s, 4H), 3.69 (br s, 4H), 2.61 - 2.52(m, 3H), 1.53 - 1.45 (m, 3H), 0.98 - 0.78 (m, 4H). [M+H] = 399.3.

Example 36.6-Methyl-N-(1-Methylcyclopropyl)-5-r2-(Trifluoromethyl)-5H,6H,7H-Pyrrolo[3,4-d]Pyrimidine-6-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 9.09 - 8.70 (m, 1H), 8.38 (s, 1H), 5.33 - 4.95(m, 4H), 2.66 (s, 3H), 1.48 (s, 3H), 0.94 - 0.77 (m, 4H). [M+H] = 419.3.

Example 37.5-[2-(4-Fluorophenyl)-5H,6H,7H,8H,-Pyrrolo[3,4-d]Pyrimidine-6-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.94 - 8.66 (m, 1H), 8.54 - 8.41 (m, 2H),8.41 - 8.37 (m, 1H), 7.21 (t, J = 8.0 Hz, 2H), 5.33 - 4.88 (m, 4H),2.72 - 2.62 (m, 3H), 1.48 (s, 3H), 0.96 - 0.77 (m, 4H). [M+H] = 445.4.

Example 38.5-{3-[3-Fluoro-5-(Trifluoromethyl)Pyridin-2-yl]Azetidine-1-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1H), 8.37 (s, 1H), 7.99 (dd, J = 1.7,9.5 Hz, 1H), 4.73 - 4.62 (m, 2H), 4.61 - 4.32 (m, 3H), 2.63 (s, 3H),1.53 (s, 3H), 1.02 - 0.81 (m, 4H). [M+H] = 450.3.

Example 39.6-Methyl-5-{2-methyl-5H,6H,7H,8H-pyridor[4,3-d]pyrimidine-6-carbonyl}-N-(1-methylcyclopropyl)furor[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.52 (br s, 1H), 8.39 (s, 1H), 4.89 (br s,2H), 4.21 - 3.80 (m, 2H), 3.11 - 3.01 (m, 2H), 2.65 (s, 3H), 2.58 (s,3H), 1.47 (s, 3H), 0.85 (s, 4H). [M+H] = 379.3.

Example 40.5-(5-Methoxy-1,2,3,4-Tetrahydro-2,6-Naphthyridine-2-Carbonyl)-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.94 (d, J = 5.4 Hz, 1H), 6.80(br s, 1H), 4.83 (br s, 2H), 3.96 (s, 5H), 2.83 (t, J = 5.0 Hz, 2H),2.56 (s, 3H), 1.51 - 1.45 (m, 3H), 0.86 (s, 4H). [M+H] = 394.3.

Example 41.5-{2-Tert-Butyl-5H,6H,7H,8H-Pyrido[4,3-d]Pyrimidine-6-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.50 (br s, 1H), 8.38 (s, 1H), 4.86 (d, J =4.2 Hz, 2H), 4.03 (br s, 2H), 3.12 - 3.01 (m, 2H), 2.58 (s, 3H), 1.46(s, 3H), 1.38 (s, 9H), 0.82 (s, 4H). [M+H] = 421.4.

Example 42.6-Methyl-N-(1-Methylcyclopropyl)-5-[4-(Pyridin-2-yl)Piperazine-1-Carbonyl]furo2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.45 - 8.39 (m, 1H), 8.09 (ddd, J = 1.7, 7.2,9.2 Hz, 1H), 8.02 (dd, J = 1.3, 6.3 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H),7.14 - 6.98 (m, 1H), 3.96 (d, J = 4.3 Hz, 4H), 3.92 - 3.81 (m, 4H),2.63 - 2.55 (m, 3H), 1.52 (s, 3H), 1.00 - 0.86 (m, 4H). [M+H] = 393.4.

Example 43.5-[4-(5-Fluoropyridin-2-yl)Piperazine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.46 - 8.41 (m, 1H), 8.09 - 8.00 (m, 1H), 7.52(ddd, J = 3.1, 7.9, 9.4 Hz, 1H), 6.97 (dd, J = 3.4, 9.4 Hz, 1H), 3.84(br s, 4H), 3.63 (br s, 4H), 2.59 (s, 3H), 1.52 (s, 3H), 1.03 - 0.84 (m,4H). [M+H] = 411.3.

Example 44.6-Methyl-N-(1-Methylcyclopropyl)-5-[4-(5-Methylpyridin-2-yl)Piperazine-1-Carbonyl]Furo[2,3-d]Pyrimidin-4-aMine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.99 (dd, J = 2.1, 9.4 Hz, 1H),7.84 (s, 1H), 7.35 (d, J = 9.4 Hz, 1H), 3.95 (br s, 4H), 3.83 (br s,4H), 2.59 (s, 3H), 2.32 (s, 3H), 1.56 - 1.49 (m, 3H), 0.97 - 0.78 (m,4H). [M+H] = 407.4.

Example 45.5-{2-Methoxy-5H,6H,7H,8H-Pyridor[4,3-d]Pyrimidine-6-Carbonyl}-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.41 (br s, 1H), 4.11 - 3.92 (m,5H), 3.35 (d, J = 1.7 Hz, 2H), 3.12 - 2.98 (m, 2H), 2.63 (s, 3H), 1.51(s, 3H), 1.02 - 0.94 (m, 4H). [M+H] = 395.3.

Example 46.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[5-(Morpholin-4-yl)Pyridin-2-yl]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.03 (d, J = 2.9 Hz, 1H), 7.87(d, J = 9.3 Hz, 1H), 7.75 (dd, J = 3.1, 9.3 Hz, 1H), 3.90 - 3.83 (m,4H), 3.28 - 3.23 (m, 4H), 2.80 (s, 3H), 1.52 (s, 3H), 1.01 - 0.85 (m,4H). [M+H] = 409.4.

Example 47.4-(4-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}Piperazin-1-yl)Benzonitrile

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.62 - 7.50 (m, 2H), 7.05 (d, J= 9.0 Hz, 2H), 3.85 (br s, 4H), 3.60 - 3.41 (m, 4H), 2.56 (s, 3H), 1.50(s, 3H), 0.97 - 0.82 (m, 4H). [M+H] = 417.4.

Example 48.N-[(4-Fluorophenyl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 7.46 - 7.36 (m, 2H), 7.14 - 7.02(m, 2H), 4.63 - 4.53 (m, 2H), 2.65 (s, 3H), 1.50 (s, 3H), 0.92 - 0.81(m, 4H). [M+H] = 355.3.

Example 49.N-[(5-Fluoropyridin-2-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J = 2.9 Hz, 1H), 8.38 (s, 1H), 7.70 -7.61 (m, 1H), 7.52 (dd, J = 4.4, 8.7 Hz, 1H), 4.73 (s, 2H), 2.77 (s,3H), 1.52 (s, 3H), 0.99 - 0.83 (m, 4H). [M+H] = 356.2.

Example 50.N-[2-(4-Fluorophenyl)Ethyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.19 (br s, 1H), 7.30 (dd, J =5.4, 8.6 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H), 3.76 - 3.57 (m, 2H), 2.95(t, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.51 (s, 3H), 0.97 - 0.81 (m, 4H).[M+H] = 369.3.

Example 51.N-[1-(5-Fluoropyridin-2-yl)Ethyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J = 2.8 Hz, 1H), 8.34 (s, 1H), 7.67 -7.59 (m, 1H), 7.51 (dd, J = 4.4, 8.7 Hz, 1H), 5.29 (q, J = 7.0 Hz, 1H),2.83 - 2.69 (m, 3H), 1.65 - 1.54 (m, 3H), 1.49 (s, 3H), 0.97 - 0.80 (m,4H). [M+H] = 370.3.

Example 52.N-[(4-Cyanophenyl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.57(d, J = 8.3 Hz, 2H), 4.68 (s, 2H), 2.79 - 2.68 (m, 3H), 1.56 - 1.46 (m,3H), 0.94 - 0.82 (m, 4H). [M+H] = 362.3.

Example 53.N-[(6-Methoxypyridin-2-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) 5 8.37 (s, 1H), 7.70 - 7.62 (m, 1H), 6.97 (d, J= 7.3 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.64 (s, 2H), 3.91 (s, 3H),2.78 (s, 3H), 1.56 - 1.45 (m, 3H), 0.95 -0.81 (m, 4H). [M+H] = 368.3.

Example 54.N-[(6-Methoxypyridin-3-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) 5 8.37 (s, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.77(dd, J = 2.4, 8.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.54 (s, 2H), 3.92(s, 3H), 2.72 - 2.64 (m, 3H), 1.51 (s, 3H), 0.97 - 0.86 (m, 4H). [M+H] =368.3.

Example 55.N-[(5-Methoxypyridin-2-yl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.76 -7.70 (m, 1H), 7.67 - 7.62 (m, 1H), 4.75 (s, 2H), 3.96 (s, 3H), 2.77 (s,3H), 1.51 (s, 3H), 0.94 - 0.86 (m, 4H). [M+H] = 368.3.

Example 56.5-[3-(4-Fluorophenyl)Azetidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.45 - 7.37 (m, 2H), 7.14 - 7.06(m, 2H), 4.72 - 4.60 (m, 2H), 4.26 (br s, 2H), 4.14 - 3.99 (m, 1H), 2.62(s, 3H), 1.52 (s, 3H), 1.00 - 0.78 (m, 4H). [M+H] = 381.3.

Example 57.5-[3-(4-Fluorophenyl)Pyrrolidine-1-Carbonyl1-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) 5 8.37 (s, 1H), 7.47 - 7.22 (m, 2H), 7.15 - 6.97(m, 2H), 4.15 - 3.88 (m, 1H), 3.88 - 3.68 (m, 2H), 3.64 - 3.41 (m, 2H),2.57 (d, J = 14.8 Hz, 3H), 2.50 -2.00 (m, 2H), 1.54 - 1.48 (m, 3H),0.99 - 0.79 (m, 4H). [M+H] = 395.4.

Example 58.2-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}-1,2,3,4-Tetrahydroisoquinoline-6-Carbonitrile

¹H NMR (400 MHz, CD₃OD) b 8.39 (s, 1H), 7.61 (s, 1H), 7.56 (d, J = 7.9Hz, 1H), 7.37 (br s, 1H), 4.92 (br s, 2H), 3.94 (br s, 2H), 3.09 - 2.98(m, 2H), 2.55 (s, 3H), 1.47 (s, 3H), 0.84 (br s, 4H). [M+H] = 388.4.

Example 59.N-{5-(Difluoromethoxy)Pyridin-2-yl]Methyl}-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J = 2.7 Hz, 1H), 8.41 (s, 1H), 7.67(dd, J = 2.7, 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.17 - 6.72 (m,1H), 4.74 (s, 2H), 2.79 (s, 3H), 1.52 (s, 3H), 0.98 - 0.88 (m, 4H).[M+H] = 404.3.

Example 60.5-[4-(4-Fluorophenyl)Piperidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.26 (dd, J = 5.6, 8.4 Hz, 2H),7.02 (t, J = 8.8 Hz, 2H), 5.08 (s, 1H), 4.74 - 3.39 (m, 1H), 3.22 - 2.65(m, 3H), 2.55 (s, 3H), 1.95 (d, J = 11.2 Hz, 2H), 1.68 (br s, 2H), 1.52(s, 3H), 0.96 - 0.82 (m, 4H). [M+H] = 409.4.

Example 61.5-[4-4-Fluorophenyl)Piperazine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.05 - 6.97 (m, 4H), 3.85 (br s,4H), 3.26 -3.11 (m, 4H), 2.56 (s, 3H), 1.50 (s, 3H), 0.94 - 0.84 (m,4H). [M+H] = 410.4.

Example 62.5-[4-Fluoro-4-(Pyridin-2-yl)Piperidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 4.9 Hz, 1H), 8.40 (s, 1H), 7.90(dt, J = 1.7, 7.8 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.37 (ddd, J = 1.0,5.0, 7.5 Hz, 1H), 2.58 (s, 4H), 2.51 -2.17 (m, 3H), 2.10 - 1.84 (m, 2H),1.52 (s, 4H), 1.07 - 0.86 (m, 5H). [M+H] = 410.4.

Example 63.4-(4-Fluorophenyl)-1-{6-Methyl-4-r(1-Methylcyclopropyl)Amino]Furo2,3-d]Pyrimidine-5-Carbonyl}Piperidin-4-Ol

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.53 (dd, J = 5.2, 8.7 Hz, 2H),7.07 (t, J = 8.9 Hz, 2H), 4.72 - 3.41 (m, 4H), 2.56 (s, 3H), 2.17 - 1.94(m, 2H), 1.87 (br s, 2H), 1.53 (s, 3H), 0.99 - 0.83 (m, 4H). [M+H] =425.4.

Example 64. 1-(3,4-Difluorophenyl)-4-{ 6-Methyl-4-r(1-Methylcyclopropyl)Amino1furor2,3-D1pyrimidine-5-Carbonyl}Piperazin-2-One

¹H NMR (400 MHz, CD₃OD) b 8.69 (s, 1H), 8.38 (s, 1H), 7.94 (dd, J = 1.9,8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 4.39 (br s, 1H), 4.07 - 3.62 (m,3H), 2.58 (s, 3H), 2.32 (br s, 2H), 2.01 (t, J = 3.2 Hz, 1H), 1.54 (s,3H), 1.03 - 0.83 (m, 4H). [M+H] = 442.4.

Example 65.6-Methyl-N-Methylcyclopropyl)-5-[(1R,5S6S)-6-[5-(Trifluoromethyl)pyridin-2-yl]-3-Azabicyclo[3.1.0]Hexane-3-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) b 8.69 (s, 1H), 8.38 (s, 1H), 7.94 (dd, J = 1.9,8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 4.39 (br s, 1H), 4.07 - 3.62 (m,3H), 2.58 (s, 3H), 2.32 (br s, 2H), 2.01 (t, J = 3.2 Hz, 1H), 1.54 (s,3H), 1.03 - 0.83 (m, 4H). [M+H] = 458.4.

Example 66.Af-[(3-Cyanophenyl)Methyl]-6-Methyl-4-[(l-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) 6 8.36 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.59 - 7.52 (m, 1H), 4.64 (s, 2H),2.71 (s, 3H), 1.50 (s, 3H), 0.94 - 0.84 (m, 4H). [M+H] = 362.3.

Example 67.3-(4-Fluorophenyl)-1-{6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carbonyl}Pyrrolidin-3-Ol

¹H NMR (400 MHz, CD₃OD) 5 8.39 (s, 1H), 7.68 - 7.46 (m, 2H), 7.10 (td, J= 8.6, 17.3 Hz, 2H), 4.22 - 3.58 (m, 4H), 2.65 - 2.15 (m, 5H), 1.60 -1.44 (m, 3H), 1.02 - 0.83 (m, 4H). [M+H] = 411.3.

Example 68.N-[1-(4-Fluorophenyl)Ethyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo2,3-d1]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, J = 7.7 Hz, 1H), 8.32 (s, 1H), 7.52 -7.36 (m, 2H), 7.16 - 7.02 (m, 2H), 5.28 - 5.14 (m, 1H), 2.66 (s, 3H),1.58 (d, J = 7.0 Hz, 3H), 1.47 (s, 3H), 0.89 - 0.73 (m, 4H). [M+H] =369.3.

Example 69.N-[1-(4-Fluorophenyl)Cyclopropyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) 5 9.08 (s, 1H), 8.34 (s, 1H), 7.41 - 7.34 (m,2H), 7.10 -7.00 (m, 2H), 2.67 (s, 3H), 1.48 (s, 3H), 1.39 - 1.31 (m,4H), 0.83 (s, 4H). [M+H] = 381.1.

Example 70.6-Methyl-N-(1-Methylcyclopropyl)-5-[3-(Pyridin-2-yl)Pyrrolidine-1-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine.

¹H NMR (400 MHz, CD₃OD) δ 8.80 - 8.61 (m, 1H), 8.40 (s, 1H), 8.36 - 8.15(m, 1H), 7.96 - 7.62 (m, 2H), 4.23 - 4.03 (m, 1H), 4.01 - 3.75 (m, 4H),2.65 - 2.44 (m, 4H), 2.30 (d, J = 18.2 Hz, 1H), 1.52 (s, 3H), 1.02 -0.86 (m, 4H). [M+H] = 378.3.

Example 71.6-Methyl-N-(1-Methylcyclopropyl)-5-[3-(Pyridin-3-yl)Pyrrolidine-1-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 9.00 - 8.73 (m, 2H), 8.70 - 8.54 (m, 1H), 8.41(s, 1H), 8.18 - 7.96 (m, 1H), 4.30 - 4.07 (m, 1H), 4.04 - 3.60 (m, 4H),2.68 - 2.44 (m, 4H), 2.40 - 2.12 (m, 1H), 1.57 - 1.48 (m, 3H), 1.01 -0.84 (m, 4H). [M+H] = 378.3.

Example 72.6-Methyl-N-(1-Methylcyclopropyl)-5-[3-(Pyridin-4-yl)Pyrrolidine-1-Carbonyl]Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.79 (br s, 2H), 8.36 (s, 1H), 8.18 - 7.92 (m,2H), 4.31 -4.03 (m, 1H), 3.82 (br s, 4H), 2.58 (br s, 4H), 2.39 - 2.08(m, 1H), 1.50 (s, 3H), 0.96 - 0.78 (m, 4H). [M+H] = 378.3.

Example 73.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1,3-Thiazol-2-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.45 - 8.38 (m, 1H), 7.81 - 7.75 (m, 1H),7.60 - 7.57 (m, 1H), 4.97 - 4.90 (m, 2H), 2.81 - 2.74 (m, 3H), 1.52 (s,3H), 1.02 - 0.88 (m, 4H). [M+H] = 344.2.

Example 74.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1,3-Thiazol-5-Ylmethy)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 1H), 8.40 (s, 1H), 7.89 (s, 1H), 4.83(s, 2H), 2.74 - 2.66 (m, 3H), 1.53 (s, 3H), 1.06 - 0.89 (m, 4H). [M+H] =344.2.

Example 75.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1,3-Thiazol-4-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J = 2.0 Hz, 1H), 8.44 - 8.40 (m, 1H),7.58 - 7.49 (m, 1H), 4.77 (s, 2H), 2.74 (s, 3H), 1.52 (s, 3H), 1.03 -0.92 (m, 4H). [M+H] = 344.2.

Example 76.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(Pyridin-2-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.71 (d, J = 5.4 Hz, 1H), 8.40 - 8.37 (m, 1H),8.30 (dt, J = 1.5, 7.9 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.80 - 7.71(m, 1H), 4.87 (br s, 2H), 2.84 - 2.78 (m, 3H), 1.49 (s, 3H), 0.88 (d, J= 3.4 Hz, 4H). [M+H] = 338.2.

Example 77.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[1-(Pyridin-2-yl)Ethyl]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 4.6 Hz, 1H), 8.38 - 8.35 (m, 1H),8.19 (dt, J = 1.6, 7.8 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.64 (ddd, J =1.0, 6.0, 7.0 Hz, 1H), 5.33 (q, J = 7.0 Hz, 1H), 2.78 (s, 3H), 1.67 (d,J = 7.1 Hz, 3H), 1.47 (s, 3H), 0.91 - 0.76 (m, 4H). [M+H] = 352.3.

Example 78.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[2-(Pyridin-2-yl)Propan-2-yl]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.65 (dd, J = 0.9, 5.3 Hz, 1H), 8.40 - 8.34(m, 1H), 8.20 (dt, J = 1.6, 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H),7.68 - 7.57 (m, 1H), 2.81 (s, 3H), 1.86 (s, 6H), 1.46 (s, 3H), 0.90 -0.78 (m, 4H). [M+H] = 366.3.

Example 79.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[1-(Pyridin-2-yl)Cyclopropyl]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.59 (dd, J = 0.9, 5.4 Hz, 1H), 8.43 - 8.36(m, 1H), 8.14 (dt, J = 1.7, 7.9 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.57(ddd, J = 0.9, 6.0, 6.9 Hz, 1H), 2.75 (s, 3H), 1.82 - 1.73 (m, 2H),1.67 - 1.59 (m, 2H), 1.52 - 1.46 (m, 3H), 0.85 (s, 4H). [M+H] = 364.3.

Example 80.N,6-Dimethyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 3.00 - 2.93 (m, 3H), 2.70 (s,3H), 1.52 (s, 3H), 1.03 - 0.91 (m, 4H). [M+H] = 261.1.

Example 81.N,N,6-Trimethyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 3.15 (s, 6H), 2.58 - 2.48 (m,3H), 1.51 (s, 3H), 1.00 - 0.85 (m, 4H). [M+H] = 275.1.

Example 82.N-Ethyl-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 3.52 - 3.39 (m, 2H), 2.73 - 2.66(m, 3H), 1.52 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.01 - 0.89 (m, 4H).[M+H] = 275.1.

Example 83.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(Oxetan-3-yl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 3.52 - 3.39 (m, 2H), 2.73 - 2.66(m, 3H), 1.52 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.01 - 0.89 (m, 4H).[M+H] = 303.1.

Example 84.N-(5-Fluoropyridin-2-yl)-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.28 (d, J = 2.9 Hz, 1H), 8.21(dd, J = 4.0, 9.2 Hz, 1H), 7.68 (ddd, J = 3.1, 8.0, 9.1 Hz, 1H), 2.78(s, 3H), 1.51 (s, 3H), 0.96 - 0.92 (m, 2H), 0.90 - 0.86 (m, 2H). [M+H] =342.

Example 85.5-[3-(4-Fluorophenyl)-3-Methylpyrrolidine-1-Carbonyl]-6-Methyl-N-(1-Methylcyclopropyl)Furo[2,3-d]Pyrimidin-4-Amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.27(dd, J = 5.3, 8.2 Hz, 1H), 7.15 - 7.04 (m, 1H), 7.04 - 6.94 (m, 1H),4.04 - 3.54 (m, 4H), 4.04 - 3.54 (m, 4H), 2.62 - 2.49 (m, 3H), 2.48 -2.14 (m, 2H), 1.51 - 1.43 (m, 4H), 1.30 (s, 2H), 0.96 - 0.75 (m, 4H).[M+H] = 409.1.

Example 86.6-Methyl-4-[(-Methylcyclopropyl)Amino]-N-[1-(Trifluoromethyl)Cyclopropyl]furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 2.67 (s, 3H), 1.51 (s, 3H),1.48 - 1.37 (m, 2H), 1.34 - 1.25 (m, 2H), 1.00 - 0.85 (m, 4H). [M+H] =355.1.

Example 87.N-[(4-Cyano-3-Fluorophenyl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.81 - 7.70 (m, 1H), 7.38 (d, J= 9.0 Hz, 2H), 4.69 - 4.65 (m, 2H), 2.72 (s, 3H), 1.49 (s, 3H), 0.92 -0.80 (m, 4H). [M+H] = 380.

Example 88.N-[(3-Cyano-4-Fluorophenyl)Methyl]-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 7.84 - 7.73 (m, 2H), 7.37 (t, J= 8.9 Hz, 1H), 4.65 - 4.57 (m, 2H), 2.70 (s, 3H), 1.50 (s, 3H), 0.96 -0.78 (m, 4H). [M+H] = 380.0.

Example 89.6-Methyl-N-(1-Methylcyclopropyl)-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.52 (br s, 1H), 8.36 (s, 1H), 2.65 - 2.59 (m,3H), 1.52 (s, 3H), 1.46 (s, 3H), 0.99 - 0.90 (m, 4H), 0.89 - 0.85 (m,2H), 0.76 - 0.72 (m, 2H). [M+H] = 301.1.

Example 90.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(Oxetan-3-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.28 (s, 1H), 4.88 (s, 2H),4.60 - 4.51 (m, 2H), 3.72 (d, J = 6.6 Hz, 2H), 3.38 - 3.34 (m, 1H), 2.65(s, 3H), 1.51 (s, 3H), 0.88 - 0.73 (m, 4H). [M+H] = 317.1.

Example 91.N-(1-Cyanocyclobutyl)-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 2.87 - 2.77 (m, 2H), 2.74 (s,3H), 2.62 -2.53 (m, 2H), 2.30 - 2.11 (m, 2H), 1.57 - 1.50 (m, 3H),0.98 - 0.86 (m, 4H). [M+H] = 326.1.

Example 92.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1,2-Oxazol-3-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.64 (d, J = 1.7 Hz, 1H), 8.26 (s, 1H), 6.52(d, J = 1.7 Hz, 1H), 4.69 (s, 2H), 2.66 (s, 3H), 1.49 (s, 3H), 0.84 -0.73 (m, 4H). [M+H] = 328.1.

Example 93.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[(3-Methyloxetan-3-yl)Methyl]furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 4.63 (d, J = 6.1 Hz, 2H), 4.44(d, J = 6.0 Hz, 2H), 3.62 (s, 2H), 2.73 - 2.65 (m, 3H), 1.56 - 1.47 (m,3H), 1.40 (s, 3H), 0.90 - 0.70 (m, 4H). [M+H] = 331.1.

Example 94.N-[(3-Fluorooxetan-3-yl)Methyl-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.29 - 8.24 (m, 1H), 4.83 - 4.67(m, 4H), 3.96 (d, J = 19.4 Hz, 2H), 2.63 (s, 3H), 1.50 (s, 3H), 0.87 -0.73 (m, 4H). [M+H] = 335.1.

Example 95.N-(2-Methoxyethyl)-6-Methyl-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CDCl₃) δ 10.33 (br s, 1H), 8.60 (s, 1H), 6.76 (br s,1H), 3.67 (q, J = 5.1 Hz, 2H), 3.62 - 3.57 (m, 2H), 3.42 (s, 3H), 2.77 -2.73 (m, 3H), 1.53 (s, 3H), 0.99 - 0.93 (m, 4H). [M+H] = 305.1.

Example 96.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-[2-(Morpholin-4-yl)Ethyl]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.52 - 8.34 (m, 1H), 4.25 - 3.58 (m, 8H), 3.48(t, J = 6.1 Hz, 2H), 3.33 - 3.13 (m, 2H), 2.76 (s, 3H), 1.54 (s, 3H),1.02 - 0.90 (m, 4H). [M+H] = 360.1.

Example 97. 6-Methyl-N-[(2-Methyl-1,3-Thiazol-4-yl)Methyl]-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.31 (s, 1H), 4.69 (s, 2H), 2.76(s, 3H), 2.73 (s, 3H), 1.54 (s, 3H), 1.10 - 0.90 (m, 4H). [M+H] = 358.3.

Example 98.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1H-Pyrrol-2-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 10.21 (br s, 1H), 8.38 (s, 1H), 6.77 - 6.62(m, 1H), 6.09 -5.97 (m, 2H), 4.57 - 4.51 (m, 2H), 2.66 (s, 3H), 1.53 (s,3H), 1.04 - 0.88 (m, 4H). [M+H] = 326.1.

Example 99.6-Methyl-N-[(1-Methyl-1H-Pyrazol-3-yl)Methyl]-4-[(1-Methylcyclopropyl)Amino]Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.54 (d, J = 2.1 Hz, 1H), 6.27(d, J = 2.2 Hz, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 2.71 (s, 3H), 1.53 (s,3H), 1.02 - 0.91 (m, 4H). [M+H] = 341.1.

Example 100.6-Methyl-4-[(1-Methylcyclopropyl)Amino]-N-(1,3-Oxazol-4-Ylmethyl)Furo[2,3-d]Pyrimidine-5-Carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.20 (s, 1H), 7.92 (d, J = 0.9Hz, 1H), 4.55 (s, 2H), 2.71 (s, 3H), 1.52 (s, 3H), 1.01 - 0.91 (m, 4H).[M+H] = 328.

Example 101.3-(4-Fluorophenyl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}azetidin-3-ol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.63 - 7.52 (m, 2H), 7.18 - 7.09(m, 2H), 4.56 (d, J = 11.1 Hz, 2H), 4.43 - 4.35 (m, 2H), 2.63 (s, 3H),1.52 (s, 3H), 1.00 - 0.85 (m, 4H). [M+H] = 397.1.

Example 102.6-Methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 6.31(d, J = 1.8 Hz, 1H), 4.68 (s, 2H), 3.93 (s, 3H), 2.70 (s, 3H), 1.52 (s,3H), 1.01 - 0.92 (m, 4H). [M+H] = 341.1.

Example 103.5-(3-Methoxy-3-phenylazetidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.47 - 7.42 (m, 4H), 7.42 - 7.35(m, 1H), 4.59 - 4.51 (m, 2H), 4.49 - 4.42 (m, 2H), 3.07 (s, 3H), 2.61(s, 3H), 1.49 (s, 3H), 0.96 - 0.83 (m, 4H). [M+H] = 393.2.

Example 104.6-Methyl-N-(1-methylcyclobutyl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]|pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.26 (br s, 1H), 2.69 (s, 3H),2.46 - 2.35 (m, 2H), 2.21 - 2.09 (m, 2H), 2.01 - 1.89 (m, 2H), 1.58 (s,3H), 1.52 (s, 3H), 0.99 - 0.86 (m, 4H). [M+H] = 315.1.

Example 105.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methyloxetan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 1H), 4.86 (d, J = 6.6 Hz, 2H), 4.53(d, J = 6.7 Hz, 2H), 2.67 (s, 3H), 1.74 (s, 3H), 1.49 (s, 3H), 0.83 -0.72 (m, 4H). [M+H] = 317.1.

Example 106.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxolan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.68 - 4.54 (m, 1H), 4.05 - 3.91(m, 2H), 3.91 - 3.73 (m, 2H), 2.68 (s, 3H), 2.42 - 2.27 (m, 1H), 2.10 -1.93 (m, 1H), 1.52 (s, 3H), 1.03 -0.86 (m, 4H). [M+H] = 317.1.

Example 107.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methyloxolan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.17 (br s, 1H), 4.09 (d, J =9.2 Hz, 1H), 4.01 - 3.91 (m, 2H), 3.75 (d, J = 9.2 Hz, 1H), 2.68 (s,3H), 2.43 (td, J = 6.6, 13.0 Hz, 1H), 2.07 (td, J = 7.8, 12.9 Hz, 1H),1.59 (s, 3H), 1.52 (s, 3H), 1.01 - 0.88 (m, 4H). [M+H] = 331.1.

Example 108.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxan-4-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 4.24 -4.08 (m, 1H), 4.05 - 3.91 (m, 2H), 3.54 (dt, J = 1.9, 11.8 Hz, 2H), 2.69(s, 3H), 1.95 (dd, J = 2.1, 12.5 Hz, 2H), 1.69 (dq, J = 4.4, 12.0 Hz,2H), 1.51 (s, 3H), 1.00 - 0.89 (m, 4H). [M+H] = 331.1.

Example 109.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methyloxan-4-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.71 (br s, 1H), 3.86 - 3.66 (m,4H), 2.73 (s, 3H), 2.24 (d, J = 13.8 Hz, 2H), 1.77 (ddd, J = 4.6, 8.8,13.8 Hz, 2H), 1.54 (s, 3H), 1.51 (s, 3H), 0.99 - 0.83 (m, 4H). [M+H] =345.1.

Example 110.N-(2,2-Dimethyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.10 (d, J = 7.5 Hz, 1H), 4.44 -4.27 (m, 1H), 3.89 - 3.72 (m, 2H), 2.68 (s, 3H), 2.00 - 1.87 (m, 2H),1.64 - 1.43 (m, 5H), 1.34 (s, 3H), 1.26 (s, 3H), 1.00 - 0.87 (m, 4H).[M+H] = 359.1.

Example 111.6-Methyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 6.66 - 6.63 (m, 1H), 6.10 (dd, J= 1.7, 3.5 Hz, 1H), 5.99 (t, J = 3.1 Hz, 1H), 4.59 (s, 2H), 3.67 (s,3H), 2.62 (s, 3H), 1.52 (s, 3H), 0.97 -0.87 (m, 4H). [M+H] = 340.1.

Example 112.N-[(Dimethyl-1,3-oxazol-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 4.43 - 4.38 (m, 2H), 2.69 (s,3H), 2.39 (s, 3H), 2.36 (s, 3H), 1.52 (s, 3H), 1.02 - 0.89 (m, 4H).[M+H] = 356.1.

Example 113.6-Methyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 6.17 (s, 1H), 4.62 (s, 2H), 2.72(s, 3H), 2.42 (d, J = 0.6 Hz, 3H), 1.52 (s, 3H), 1.00 - 0.89 (m, 4H).[M+H] = 342.1.

Example 114.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.03 (d, J = 8.6 Hz, 2H), 3.81 -3.72 (m, 2H), 2.69 - 2.63 (m, 4H), 1.99 (t, J = 2.5 Hz, 2H), 1.52 (s,3H), 1.02 - 0.88 (m, 4H). [M+H] = 329.1.

Example 115.6-Methyl-N-(1-methyl-1H-imidazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.26 (s, 1H), 7.66 (s, 1H), 7.00(s, 1H), 4.63 (s, 2H), 3.76 (s, 3H), 2.59 (s, 3H), 1.49 (s, 3H), 0.84 -0.73 (m, 4H). [M+H] = 341.1.

Example 116.6-Methyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.35 (s, 1H), 7.56 (s, 1H), 4.65(s, 2H), 3.93 (s, 3H), 2.71 (s, 3H), 1.50 (s, 3H), 0.94 - 0.82 (m, 4H).[M+H] = 341.1.

Example 117.6-Methyl-N-(1-methylcyclopropyl)-5-(morpholine-4-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 3.73 (br s, 8H), 2.54 (s, 3H),1.52 (s, 3H), 1.00 - 0.85 (m, 4H). [M+H] = 317.1.

Example 118.6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-2-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (br s, 1H), 8.40 (s, 1H), 8.13 (br s,1H), 7.81 (br s, 1H), 7.59 (br s, 1H), 4.98 - 4.85 (m, 2H), 4.65 - 3.35(m, 5H), 2.56 (s, 3H), 1.51 (s, 3H), 1.00 -0.82 (m, 4H). [M+H] = 394.2.

Example 119.6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-4-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.83 (d, J = 5.5 Hz, 2H), 8.37 (s, 1H), 8.11(br s, 2H), 4.95 (br s, 1H), 4.81 - 4.36 (m, 1H), 4.31 - 3.37 (m, 4H),3.28 - 2.75 (m, 1H), 2.55 (br s, 3H), 1.51 (s, 3H), 0.96 - 0.80 (m, 4H).[M+H] = 394.2.

Example 120.6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-3-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.87 (br s, 1H), 8.75 (d, J = 5.4 Hz, 1H),8.51 (br s, 1H), 8.36 (s, 1H), 7.94 (d, J = 6.6 Hz, 1H), 5.02 - 4.86 (m,2H), 4.72 - 3.35 (m, 5H), 2.55 (br s, 3H), 1.55 - 1.48 (m, 3H), 0.99 -0.76 (m, 4H). [M+H] = 394.2.

Example 121.6-Methyl-5-[2-(1-methyl-1H-pyrazol-4-yl)morpholine-4-carbony]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.64 (br s, 1H), 7.49 (br s,1H), 4.77 - 3.92 (m, 4H), 3.86 (s, 3H), 3.80 - 3.35 (m, 3H), 2.54 (s,3H), 1.54 - 1.48 (m, 3H), 0.95 - 0.83 (m, 4H). [M+H] = 397.2.

Example 122.5-[2-(4-Fluorophenyl)morpholine-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.46 (br s, 2H), 7.11 (t, J =8.4 Hz, 2H), 4.77 - 3.38 (m, 6H), 3.26 - 2.91 (m, 1H), 2.55 (br s, 3H),1.56 - 1.49 (m, 3H), 0.99 - 0.84 (m, 4H). [M+H] = 411.2.

Example 123.5-[2-(4-Methoxyphenyl)morpholine-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 7.45 (br s, 2H), 6.91 (d, J =7.9 Hz, 2H), 4.45 (d, J = 12.1 Hz, 1H), 4.00 (d, J = 13.1 Hz, 2H),3.88 - 3.36 (m, 7H), 2.66 - 2.13 (m, 3H), 1.47 (br s, 3H), 0.79 (br s,4H). [M+H] = 423.2.

Example 124.N-Cyclopropyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 2.90 (tt, J = 3.8, 7.4 Hz, 1H),2.63 (s, 3H), 1.53 (s, 3H), 1.03 - 0.97 (m, 2H), 0.95 - 0.91 (m, 2H),0.90 - 0.84 (m, 2H), 0.72 - 0.65 (m, 2H). [M+H] = 287.1.

Example 125.N-(2-Fluoroethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.69 - 4.49 (m, 2H), 3.80 - 3.65(m, 2H), 2.70 (s, 3H), 1.51 (s, 3H), 0.99 - 0.89 (m, 4H). [M+H] = 293.1.

Example 126. 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1R,3R)-3-fluorocyclobutyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 5.37 - 5.13 (m, 1H), 4.73 - 4.62(m, 1H), 2.73 - 2.59 (m, 5H), 2.58 - 2.44 (m, 2H), 1.51 (s, 3H), 0.98 -0.85 (m, 4H). [M+H] = 319.1.

Example 127.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1S,3S)-3-fluorocyclobutyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 4.94 (quin, J = 6.7 Hz, 1H),4.82 - 4.74 (m, 0H), 4.15 - 3.99 (m, 1H), 2.96 - 2.82 (m, 2H), 2.70 (s,3H), 2.41 - 2.24 (m, 2H), 1.51 (s, 3H), 0.97 - 0.85 (m, 4H). [M+H] =319.1.

Example 128.N-(3,3-Difluorocyclobutyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 4.44 - 4.28 (m, 1H), 3.13 - 2.95(m, 2H), 2.84 - 2.70 (m, 2H), 2.70 - 2.66 (m, 3H), 1.50 (s, 3H), 0.96 -0.85 (m, 4H). [M+H] = 337.1.

Example 129.N-(4-Cyclopropyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.67 (s, 1H), 3.87 - 3.80 (m,2H), 3.68 (dt, J = 1.9, 11.8 Hz, 2H), 2.74 (s, 3H), 2.24 (d, J = 12.2Hz, 2H), 1.68 (ddd, J = 4.7, 11.8, 14.0 Hz, 2H), 1.57 - 1.48 (m, 4H),0.95 - 0.85 (m, 4H), 0.56 - 0.44 (m, 4H). [M+H] = 371.1.

Example 130.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-phenyloxetan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.64 - 7.57 (m, 2H), 7.48 - 7.39(m, 2H), 7.39 - 7.30 (m, 1H), 5.14 (d, J = 7.0 Hz, 2H), 4.96 (d, J = 7.1Hz, 2H), 2.83 (s, 3H), 1.44 (s, 3H), 0.85 - 0.77 (m, 4H). [M+H] = 379.1.

Example 131.5-{3-[4-(Difluoromethyl)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.59 - 7.35 (m, 4H), 6.96 - 6.50(m, 1H), 4.11 - 3.51 (m, 5H), 2.57 (d, J = 14.4 Hz, 3H), 2.50 - 2.03 (m,2H), 1.51 (s, 3H), 1.01 - 0.81 (m, 4H). [M+H] = 427.1.

Example 132.5-(3-Fluoro-3-phenylpyrrolidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.42 - 8.37 (m, 1H), 7.60 - 7.34 (m, 5H),4.27 - 3.83 (m, 4H), 2.59 (d, J = 16.1 Hz, 5H), 1.52 (s, 3H), 1.00 -0.87 (m, 4H). [M+H] = 395.1.

Example 133.5-[3-Fluoro-3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.57 (br s, 2H), 7.17 (br s,2H), 4.24 - 3.79 (m, 4H), 2.57 (d, J = 13.9 Hz, 5H), 1.50 (s, 3H),0.97 - 0.81 (m, 4H). [M+H] = 413.1.

Example 134.N-(2-Hydroxyethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 4.61 (t, J = 5.2 Hz, 1H), 3.80(t, J = 5.2 Hz, 1H), 3.77 - 3.71 (m, 2H), 3.59 - 3.52 (m, 2H), 2.74 -2.69 (m, 3H), 1.52 (s, 3H), 1.04 - 0.91 (m, 4H). [M+H] = 291.1.

Example 135.N-(4-Hydroxy-2-methylbutan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.22 - 8.09 (m, 1H), 4.53 (t, J= 6.8 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 2.72 - 2.68 (m, 3H), 2.45 -2.21 (m, 1H), 2.21 - 1.96 (m, 2H), 1.54 -1.49 (m, 9H), 1.02 - 0.92 (m,4H). [M+H] = 333.1.

Example 136.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(propan-2-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.07 (d, J = 6.2 Hz, 1H), 4.31 -4.15 (m, 1H), 2.67 (s, 3H), 1.52 (s, 3H), 1.29 (d, J = 6.6 Hz, 6H),0.98 - 0.86 (m, 4H). [M+H] = 289.1.

Example 137.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylpropyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.25 (br s, 1H), 3.25 (t, J =6.4 Hz, 2H), 2.68 (s, 3H), 1.93 (quind, J = 6.8, 13.5 Hz, 1H), 1.50 (s,3H), 0.99 (d, J = 6.7 Hz, 6H), 0.93 -0.83 (m, 4H). [M+H] = 303.1.

Example 138.N-tert-Butyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.30 (s, 1H), 7.72 (br s, 1H), 2.63 (s, 3H),1.51 (s, 3H), 1.47 (s, 9H), 0.92 - 0.82 (m, 4H). [M+H] = 303.1.

Example 139.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxan-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.30 (br s, 1H), 3.99 (dd, J =2.9, 11.3 Hz, 2H), 3.45 (dt, J = 2.1, 11.8 Hz, 2H), 3.39 - 3.34 (m, 2H),2.73 (s, 3H), 2.01 - 1.88 (m, 1H), 1.72 (dd, J = 1.8, 13.0 Hz, 2H), 1.54(s, 3H), 1.46 - 1.32 (m, 2H), 1.04 - 0.90 (m, 4H). [M+H] = 345.1.

Example 140.N-(4-Ethyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.68 (s, 1H), 3.86 - 3.78 (m,2H), 3.75 -3.64 (m, 2H), 2.72 (s, 3H), 2.24 (d, J = 13.4 Hz, 2H), 2.05 -1.94 (m, 2H), 1.76 - 1.65 (m, 2H), 1.54 - 1.46 (m, 3H), 0.89 (t, J = 7.5Hz, 3H), 0.84 (s, 4H). [M+H] = 359.1.

Example 141.6-Methyl-N-(1-methyl-1H-pyrazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.07 (s, 1H), 7.64 (s, 1H), 3.91(s, 3H), 2.74 (s, 3H), 1.55 - 1.48 (m, 3H), 1.00 - 0.85 (m, 4H). [M+H] =327.1.

Example 142.6-Methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 6.71 (d, J = 0.9 Hz, 1H), 2.73(s, 3H), 2.46 (d, J = 0.9 Hz, 3H), 1.52 (s, 3H), 0.95 - 0.89 (m, 2H),0.88 - 0.82 (m, 2H). [M+H] = 328.1.

Example 143.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-2-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.42 (d, J = 4.4 Hz, 1H), 7.08(d, J = 4.4 Hz, 1H), 2.92 (s, 3H), 1.56 (s, 3H), 1.02 - 0.92 (m, 4H).[M+H] = 330.

Example 144.N-(5-Methoxypyridin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.09 - 8.04 (m, 2H), 7.50 (dd, J= 3.2, 9.0 Hz, 1H), 3.90 (s, 3H), 2.77 (s, 3H), 1.51 (s, 3H), 0.95 -0.80 (m, 4H). [M+H] = 354.1.

Example 145.N-(1-Ethylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.49 (br s, 1H), 8.37 (s, 1H), 2.65 (s, 3H),1.74 (q, J = 7.4 Hz, 2H), 1.53 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H), 0.99 -0.91 (m, 4H), 0.89 - 0.84 (m, 2H), 0.80 -0.74 (m, 2H). [M+H] = 315.1.

Example 146.N-[1-(Hydroxymethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 3.69 (s, 2H), 2.68 (s, 3H), 1.53(s, 3H), 1.07 - 0.86 (m, 8H). [M+H] = 317.

Example 147.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (br s, 1H), 8.36 (s, 1H), 2.66 (s, 3H),1.65 (spt, J = 6.8 Hz, 1H), 1.51 (s, 3H), 1.03 (d, J = 6.8 Hz, 6H),0.98 - 0.78 (m, 8H). [M+H] = 329.1.

Example 148.N-[1-(Methoxymethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.50 (br s, 1H), 8.35 (s, 1H), 3.56 (s, 2H),3.41 (s, 3H), 2.64 (s, 3H), 1.52 (s, 3H), 0.99 - 0.86 (m, 8H). [M+H] =331.1.

Example 149.N-(1-Cyclopropylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.61 (br s, 1H), 8.35 (s, 1H), 2.63 (s, 3H),1.58 - 1.46 (m, 4H), 1.00 - 0.87 (m, 4H), 0.85 - 0.69 (m, 4H), 0.51 -0.45 (m, 2H), 0.33 - 0.26 (m, 2H). [M+H] = 327.1.

Example 150.N-(1-Cyclobutylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.56 (br s, 1H), 8.34 (s, 1H), 2.85 - 2.74 (m,1H), 2.63 (s, 3H), 2.04 - 1.89 (m, 2H), 1.87 - 1.75 (m, 3H), 1.74 - 1.65(m, 1H), 1.51 (s, 3H), 0.97 - 0.86 (m, 4H), 0.86 - 0.79 (m, 4H). [M+H] =341.1.

Example 151.N-[3-(4-Fluorophenyl)cyclobutyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.48 - 8.40 (m, 1H), 8.36 (s, 1H), 7.41 - 7.24(m, 2H), 7.12 - 6.97 (m, 2H), 4.70 - 4.41 (m, 1H), 3.29 - 3.21 (m, 1H),2.83 (dq, J = 2.8, 7.9 Hz, 2H), 2.76 - 2.68 (m, 3H), 2.65 - 2.55 (m,1H), 2.27 - 2.14 (m, 2H), 1.55 - 1.49 (m, 3H), 1.02 - 0.84 (m, 4H).[M+H] = 395.2.

Example 152.5-[4-(3-Fluoropyridin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.44(ddd, J = 1.4, 7.9, 13.2 Hz, 1H), 6.92 (ddd, J = 3.2, 4.8, 8.0 Hz, 1H),3.85 (br s, 4H), 3.55 (br s, 4H), 2.57 (s, 3H), 1.51 (s, 3H), 0.96 -0.84 (m, 4H). [M+H] = 411.2.

Example 153.5-[4-(5-Fluoropyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.32 (s, 2H), 4.05 - 3.56 (m,8H), 2.55 (s, 3H), 1.50 (s, 3H), 0.94 - 0.78 (m, 4H). [M+H] = 412.2.

Example 154.5-[4-(6-Fluoropyridin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.66 (q, J = 8.2 Hz, 1H), 6.65(dd, J = 2.4, 8.2 Hz, 1H), 6.25 (dd, J = 2.8, 7.8 Hz, 1H), 3.79 (br s,4H), 3.66 (br s, 4H), 2.55 (s, 3H), 1.50 (s, 3H), 0.93 - 0.79 (m, 4H).[M+H] = 411.2.

Example 155.5-[(3aS,6aS)-Hexahydro-2H-furo[3,2-b]pyrrole-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 4.89 (br s, 1H), 4.56 (t, J =4.3 Hz, 1H), 4.05 - 3.82 (m, 2H), 3.77 - 3.59 (m, 2H), 2.55 (s, 3H),2.50 - 2.34 (m, 1H), 2.19 - 2.06 (m, 2H), 2.05 - 1.92 (m, 1H), 1.51 (s,3H), 1.01 - 0.84 (m, 4H). [M+H] = 343.1.

Example 156.5-[4-(2-Fluorophenyl)-1,4-diazepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.33 (br s, 1H), 7.20 - 6.54 (m, 4H), 4.10 -3.65 (m, 4H), 3.62 - 3.34 (m, 4H), 2.47 (br s, 3H), 2.24 - 1.74 (m, 2H),1.40 (br s, 3H), 0.89 - 0.53 (m, 4H). [M+H] = 424.1.

Example 157.6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenyl-1,4-diazepane-1-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 6.86 (t, J = 7.6 Hz, 2H), 6.55(d, J = 7.8 Hz, 2H), 6.47 - 6.32 (m, 1H), 4.22 - 3.49 (m, 8H), 2.45 (s,3H), 2.25 - 1.67 (m, 2H), 1.42 (s, 3H), 0.92 - 0.68 (m, 4H). [M+H] =406.1.

Example 158.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyridin-2-yl)-1,4-diazepane-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.83 (br s, 2H), 7.41 - 6.69 (m,2H), 4.18 -3.53 (m, 8H), 2.45 (s, 3H), 2.27 - 1.64 (m, 2H), 1.41 (s,3H), 0.84 - 0.58 (m, 4H). [M+H] = 407.1.

Example 159.5-[4-(4-Methoxyphenyl)-1,4-diazepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 7.08 - 5.84 (m, 4H), 4.61 - 3.45(m, 8H), 2.47 (s, 3H), 2.29 - 1.51 (m, 2H), 1.46 - 1.36 (m, 3H), 1.02 -0.60 (m, 4H). [M+H] = 436.1.

Example 160.5-[4-(2-fluoropyridin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.85 (d, J = 6.4 Hz, 1H), 6.86 -6.80 (m, 1H), 6.51 (t, J = 2.3 Hz, 1H), 3.85 (br s, 4H), 3.61 (br s,4H), 2.57 (s, 3H), 1.50 (s, 3H), 0.94 -0.81 (m, 4H). [M+H] = 411.

Example 161.5-[4-(6-Fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 6.42(d, J = 1.2 Hz, 1H), 3.82 (br s, 8H), 2.57 (s, 3H), 1.55 - 1.49 (m, 3H),0.98 - 0.86 (m, 4H). [M+H] = 412.

Example 162.5-[4-(2-Fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.09 (dd, J = 2.7, 6.2 Hz, 1H),6.74 (dd, J = 4.4, 6.1 Hz, 1H), 3.83 (br s, 8H), 2.57 (s, 3H), 1.51 (s,3H), 0.96 - 0.91 (m, 2H), 0.89 - 0.84 (m, 2H). [M+H] = 412.

Example 163.N-[(3-Fluoropyridin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J = 1.5 Hz, 1H), 8.43 (d, J = 5.0 Hz,1H), 8.41 (s, 1H), 7.62 (t, J = 5.8 Hz, 1H), 4.77 (s, 2H), 2.77 (s, 3H),1.50 (s, 3H), 0.98 - 0.87 (m, 4H). [M+H] = 356.

Example 164.N-[(2-Fluoropyridin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.18 (d, J = 5.3 Hz, 1H), 7.32(d, J = 5.0 Hz, 1H), 7.06 (s, 1H), 4.66 (s, 2H), 2.69 (s, 3H), 1.47 (s,3H), 0.79 - 0.71 (m, 4H). [M+H] = 356.1.

Example 165.N-Cyclopentyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 315.2.

Example 166.1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}pyrrolidin-3-ol

[M+H] = 317.2.

Example 167.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-pentylfuro[2,3-d]pyrimidine-5-carboxamide

[M+H] = 317.4.

Example 168.6-Methyl-N-(3-methylbutyl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 317.4.

Example 169.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pentan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 317.4.

Example 170.6-Methyl-N-(3-methylbutan-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 317.2.

Example 171.N-(2-Rthoxyethyl)-6-methyl-4-[(1-methylcyclopropy)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 319.2.

Example 172.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-4-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 324.2.

Example 173.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 324.2.

Example 174.6-Methyl-N-(1-methyl-1H-pyrazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 6.36(d, J = 2.1 Hz, 1H), 3.80 (s, 3H), 2.84 (s, 3H), 1.51 (s, 3H), 1.02 -0.86 (m, 4H). [M+H] = 327.2.

Example 175.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxolan-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 331.2.

Example 176.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(propan-2-yloxy)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 333.3.

Example 177.N-Benzyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 337.2.

Example 178.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 337.2.

Example 179.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 337.3.

Example 180.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 337.2.

Example 181.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylpyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 338.2.

Example 182.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(1H-pyrrol-1-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 340.2.

Example 183.N-(3-Fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 341.4.

Example 184.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(morpholin-4-yl)phenyl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 422.6.

Example 185.N-[(2,3-Difluoro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 403.5.

Example 186.5-[4-(4-Methoxyphenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 422.5.

Example 187.N-(2-Fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 341.2.

Example 188.N[2-(Furan-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 341.2.

Example 189.N-[2-(1H-Imidazol-1-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 341.2.

Example 190.6-Methyl-4-(1-methylcyclopropyl)amino]-N-(thiophen-2-ylmethy)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 343.2.

Example 191.6-Methyl-4-(1-methylcyclopropyl)amino]-N-(thiophen-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 343.2.

Example 192.N-(Cyclohexylmethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 343.3.

Example 193.6-Methyl-4-[(1-methyleyelopropyl)amino]-N-(1-methylpiperidin-4-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 344.3.

Example 194.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 351.3.

Example 195.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 351.3.

Example 196.6-Methyl-4-r(1-methylcyclopropyl)amino]-N[(4-methylphenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 351.3.

Example 197.N-(2,5-Dimethylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 351.3.

Example 198.6-Methyl-4-[(1-methyleyelopropyl)amino]-N-[(3-methylphenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 351.3.

Example 199.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-phenylfuror2,3-d]pyrimidine-5-carboxamide

[M+H] = 323.2.

Example 200.5-[(1R,5S)-3-Azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 313.4.

Example 201. 5-[(3aR,6aS)-Octahydrocyclopenta[pyrrole-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 341.5.

Example 202.N,N-Dimethyl-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-amine

[M+H] = 358.5.

Example 203.N-[(3-Methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.3.

Example 204.N-[2-(3-Chlorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 205.N-[2-(4-Methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 395.3.

Example 206.6-Methyl-5-(4-methyl-1,4-diazepane-1-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 344.3.

Example 207.N-[2-(5-Fluoro-1H-indol-3-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 408.3.

Example 208.6-Methyl-N-(1-methylcyclopropyl)-5-[(1R,5S,6S)-6-phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]furor2,3-d]pyrimidin-4-amine

[M+H] = 389.3.

Example 209.5-[(1R,5S,6S)-6-(2-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 419.3.

Example 210.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-1-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 285.1.

Example 211.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-propylfuro[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 9.25 - 9.03 (m, 1H), 8.48 (s, 1H), 6.03 - 5.89(m, 1H), 3.52 - 3.42 (m, 2H), 2.71 (s, 3H), 1.70 (d, J = 7.2 Hz, 2H),1.54 (s, 3H), 1.04 (t, J = 7.5 Hz, 3H), 0.95 - 0.79 (m, 4H). [M+H] =289.2.

Example 212.N-Cyclobutyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-dlpyrimidine-5-carboxamide

[M+H] = 301.4.

Example 213.N-Butyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 303.4.

Example 214.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 352.4.

Example 215.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 352.5.

Example 216.N-(3-Methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 353.4.

Example 217.N-[(3-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

[M+H] = 355.4.

Example 218.N[(2-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 355.4.

Example 219.N-(3-Fluoro-4-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 355.4.

Example 220.N-[3-(1H-Imidazol-1-yl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 355.4.

Example 221.5-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 356.5.

Example 222.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(thiophen-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 357.4.

Example 223.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 357.4.

Example 224.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 357.4.

Example 225.N-(2-Cyclohexylethyl)-6-methyl-4-[(1-methyleyelopropyl)aminolfuro[2,3-d]pyrimidine-5-carboxamide

[M+H] = 357.5.

Example 226.1-(4-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperazin-1-yl)ethan-1-one

[M+H] = 358.4.

Example 227.N-(3,4-Difluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 359.4.

Example 228.N-(3,5-Difluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 359.4.

Example 229.N-(2,3-Dihydro-1H-inden-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 363.5.

Example 230.N-(2,3-Dihydro-1H-inden-1-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 363.4.

Example 231.N-(2,3-Dihydro-1H-inden-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 363.5.

Example 232.N-(2,3-Dihydro-1H-inden-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 363.5.

Example 233.b-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)furor2,3-d1pyrimidin-4-amine

[M+H] = 363.5.

Example 234.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[4-(propan-2-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 235.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(4-methylphenyl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 236.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(2-methylphenyl)ethy]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 237.N-[(3,4-Dimethylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 238.N-[(2,3-Dimethylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 239.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-phenylpropan-2-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 240.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino1-N-(2-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 241.N-Benzyl-N-ethyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 365.5.

Example 242.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino1-N-[2-(pyridin-2-yl)ethyllfuro[2,3-d]pyrimidine-5-carboxamide

[M+H] = 366.4.

Example 243.N-(2H-1,3-Benzodioxol-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 367.4.

Example 244.N-(4-Methoxy-2-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 367.5.

Example 245.N-(3-Methoxy-2-methylphenyl)-6-methyl-4-[(l-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 367.4.

Example 246.N-[(3-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 367.5.

Example 247.5-[2-(Furan-2-yl)]pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 367.5.

Example 248.N-[(4-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.4.

Example 249.N-[(2-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.5.

Example 250.N-[(3-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.4.

Example 251.N-[(3-Ethyl-1,2-oxazol-5-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 370.5.

Example 252.N-(5-Fluoro-2-methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.4.

Example 253.N-(4-Fluoro-3-methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.4.

Example 254.N-[(2-Chlorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.4.

Example 255.N-(2-Chloro-4-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.4.

Example 256.N-(2-Chloro-5-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.4.

Example 257.1-(4-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,4-diazepan-1-yl)ethan-1-one

[M+H] = 372.5.

Example 258.5-(4-tert-Butylpiperazine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 372.5.

Example 259.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[3-(morpholin-4-yl)propyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 374.5.

Example 260.5-[4-(2-Methoxyethyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 374.5.

Example 261.N-(4-Chloro-2-fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 375.4.

Example 262.6-Methyl-N-(1-methyl-1H-indazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 377.4.

Example 263.N-(1,3-Benzothiazol-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 380.4.

Example 264.N-(1,3-Benzothiazol-6-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 380.4.

Example 265.N(5-Cyclopropyl-1H-pyrazol-3-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.5.

Example 266.N-(2,2-Dimethyloxan-4-yl)-N-ethyl-6-methyl-4-f(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 387.5.

Example 267.N-{[4-(Difluoromethoxy)phenyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 403.4.

Example 268.N-[3-Methoxy-5-(trifluoromethyl)phenyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 421.5.

Example 269.5-{5H,6H,7H,8H-Imidazo[1,2-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 353.4.

Example 270.N-(Adamantan-1-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.5.

Example 271.5-[(4aS,8aR)-Decahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 369.5.

Example 272.6-Methyl-4-[(1-methylcyclopropyl)amino1-N-(6-methylpyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 338.4.

Example 273.6-Methyl-N-(1-methylcyclopropyl)-5-{4H,5H,6H,7H-thieno[3,2-c]pyridine-5-carbonyl}furo[2,3-d]pyrimidin-4-amine

[M+H] = 369.4.

Example 274.1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-4-phenylpiperidine-4-carbonitrile

[M+H] = 416.5.

Example 275.N-{[1-(Ethoxymethyl)cyclopropyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 359.5.

Example 276.6-Methyl-N-(1-methylcyclopropyl)-5-{5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl}furo[2,3-d]pyrimidin-4-amine

[M+H] = 350.4.

Example 277.N-(Adamantan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.5.

Example 278.5-{6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 341.5.

Example 279.5-[(1R,5S,6S)-6-(4-Fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 407.5.

Example 280.N-[(6-Fluoropyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.94 (q, J = 8.1 Hz, 1H), 7.34(dd, J = 2.2, 7.3 Hz, 1H), 6.97 (dd, J = 2.4, 8.1 Hz, 1H), 4.68 (s, 2H),2.79 (s, 3H), 1.50 (s, 3H), 0.95 - 0.85 (m, 4H). [M+H] = 355.90.

Example 281.N-[1-(5-Fluoropyridin-2-yl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.51(dt, J = 2.9, 8.6 Hz, 1H), 7.39 (dd, J = 4.2, 8.9 Hz, 1H), 2.74 (s, 3H),1.70 - 1.62 (m, 2H), 1.49 (s, 3H), 1.44 -1.36 (m, 2H), 0.91 - 0.85 (m,4H). [M+H] = 382.

Example 282.5-[4-(6-Fluoropyridin-3-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.86 (br s, 1H), 7.66 (ddd, J =3.1, 6.5, 9.2 Hz, 1H), 7.00 (dd, J = 3.1, 9.0 Hz, 1H), 3.89 (br s, 4H),3.29 (br s, 4H), 2.59 (s, 3H), 1.53 (s, 3H), 0.97 - 0.85 (m, 4H). [M+H]= 411.

Example 283.6-Methyl-5-(7-methyl-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.37 (s, 1H), 7.74 (br s, 1H),5.11 (br s, 2H), 4.32 - 3.70 (m, 2H), 3.12 (t, J = 5.4 Hz, 2H), 2.72 (s,3H), 2.58 (s, 3H), 1.47 (s, 3H), 0.87 - 0.76 (m, 4H). [M+H] = 378.1.

Example 284.6-Methyl-5-(2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.71(d, J = 8.2 Hz, 1H), 5.01 (br s, 2H), 4.09 (br s, 2H), 2.75 (s, 3H),2.60 - 2.56 (m, 3H), 1.47 (s, 4H), 0.88 -0.77 (m, 5H). [M+H] = 378.

Example 285.5-(5-Chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.25(br s, 1H), 4.91 (br s, 2H), 4.01 (br s, 2H), 3.00 (t, J = 5.3 Hz, 2H),2.57 (s, 3H), 1.47 (s, 3H), 0.84 (s, 4H). [M+H] = 397.9.

Example 286.5-(2-Chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.31(d, J = 8.1 Hz, 1H), 4.85 - 4.73 (m, 2H), 4.14 - 3.77 (m, 2H), 2.99 (brs, 2H), 2.57 (s, 3H), 1.47 (s, 3H), 0.84 (d, J = 5.1 Hz, 4H). [M+H] =397.9.

Example 287.5-(2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.31(d, J = 7.9 Hz, 1H), 4.87 (br s, 2H), 4.02 (br s, 2H), 3.06 (br s, 2H),2.56 (s, 3H), 1.47 (s, 3H), 0.83 (s, 4H). [M+H] = 397.9.

Example 288.5-{3-Chloro-5H,6H,7H,8H-pyrido[4,3-c]pyridazine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.69 (br s, 1H), 4.97 (br s,2H), 4.07 (br s, 2H), 2.59 (s, 3H), 1.47 (s, 4H), 0.90 - 0.81 (m, 5H).[M+H] = 398.9.

Example 289.5-{2-Chloro-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.51 (br s, 1H), 8.40 (s, 1H), 4.91 (br s,2H), 4.02 (br s, 2H), 3.08 (t, J = 5.4 Hz, 2H), 2.59 (s, 3H), 1.47 (s,3H), 0.90 - 0.82 (m, 4H). [M+H] = 398.9.

Example 290.6-Methyl-N-(1-methylcyclopropyl)-5-[2-(oxan-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbony]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.70(d, J = 8.3 Hz, 1H), 4.99 (br s, 2H), 4.39 - 3.78 (m, 4H), 3.57 (dt, J =2.9, 11.5 Hz, 2H), 3.19 (ddd, J = 4.5, 11.1, 16.0 Hz, 1H), 2.57 (s, 3H),1.98 - 1.83 (m, 4H), 1.46 (s, 3H), 0.78 (br s, 4H). [M+H] = 448.

Example 291.N-[(2-Fluoropyridin-3-yl)methyl]-6-methyl-4-{(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.99(ddd, J = 1.8, 7.5, 9.7 Hz, 1H), 7.34 (ddd, J = 1.7, 5.1, 7.2 Hz, 1H),4.65 (s, 2H), 2.71 (s, 3H), 1.51 (s, 3H), 0.97 - 0.83 (m, 4H). [M+H] =355.9.

Example 292.N-(5-Fluoropyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 2H), 8.38 (s, 1H), 4.84 (br s, 2H),2.82 (s, 3H), 1.51 (s, 3H), 0.96 - 0.83 (m, 4H). [M+H] = 356.9.

Example 293.N-[(6-Fluoropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.75 (br s, 1H), 8.37 (s, 1H), 8.25 (d, J =2.2 Hz, 1H), 8.00 (dt, J = 2.5, 8.1 Hz, 1H), 7.08 (dd, J = 2.5, 8.5 Hz,1H), 4.66 - 4.58 (m, 2H), 2.70 (s, 3H), 1.51 (s, 3H), 0.95 - 0.87 (m,4H). [M+H] = 355.9.

Example 294.6-Methyl-N-(1-methyleyelopropyl)-5-[2-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.40 (s, 1H), 4.95 - 4.86 (m,2H), 3.99 (br s, 2H), 3.22 - 3.09 (m, 1H), 2.98 (br s, 2H), 2.59 (s,3H), 1.48 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H), 0.90 - 0.83 (m, 4H). [M+H]= 407.

Example 295.5-[3-(4-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.45 - 6.79 (m, 4H), 4.27 - 3.35(m, 4H), 3.23 - 3.00 (m, 1H), 2.57 - 2.34 (m, 3H), 2.23 - 1.67 (m, 5H),1.53 (s, 3H), 1.44 - 1.23 (m, 1H), 1.01 - 0.83 (m, 4H). [M+H] = 423.

Example 296.5-[4-(4-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.27 - 7.09 (m, 2H), 7.04 - 6.90(m, 2H), 4.23 - 3.73 (m, 2H), 3.73 - 3.40 (m, 2H), 2.85 - 2.59 (m, 1H),2.53 (s, 3H), 2.20 - 1.62 (m, 6H), 1.53 (s, 3H), 0.99 - 0.82 (m, 4H).[M+H] = 423.

Example 297.N-[1-(2-Hydroxyethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.43 (br s, 1H), 8.41 - 8.36 (m, 1H), 3.75 (t,J = 6.5 Hz, 2H), 2.66 (s, 3H), 1.90 (t, J = 6.6 Hz, 2H), 1.53 (s, 3H),1.01 - 0.96 (m, 2H), 0.96 - 0.90 (m, 4H), 0.88 - 0.82 (m, 2H). [M+H] =331.

Example 298.N-[1-(3-Fluoro-4-methoxyphenyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 8.36 (s, 1H), 7.15 - 6.99 (m,3H), 3.87 -3.83 (m, 3H), 2.67 (s, 3H), 1.48 (s, 3H), 1.39 - 1.28 (m,4H), 0.86 (s, 4H). [M+H] = 411.

Example 299.5-{2-Cyclopropyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-6]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 8.38 (s, 1H), 4.81 (br s, 2H),3.97 (br s, 2H), 2.94 (br s, 2H), 2.57 (s, 3H), 2.23 - 2.11 (m, 1H),1.47 (s, 3H), 1.13 - 1.02 (m, 4H), 0.93 - 0.78 (m, 4H). [M+H] = 405.1.

Example 300.6-Methyl-4-[(1-methylcyclopropyl)amino1-N-[1-(oxan-4-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.36 (s, 1H), 3.96 (dd, J = 4.4,11.5 Hz, 2H), 3.42 - 3.34 (m, 2H), 2.66 (s, 3H), 1.77 - 1.69 (m, 2H),1.63 - 1.55 (m, 1H), 1.53 - 1.42 (m, 5H), 0.95 - 0.90 (m, 4H), 0.88 (s,4H). [M+H] = 371.1.

Example 301.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyridin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.77 (dd, J = 1.0, 5.7 Hz, 1H), 8.52 (dt, J =1.6, 7.9 Hz, 1H), 8.42 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.90 (ddd, J =1.1, 6.0, 7.4 Hz, 1H), 4.81 - 3.88 (m, 2H), 3.60 - 3.34 (m, 2H), 3.30 -3.08 (m, 1H), 2.60 (s, 3H), 2.27 - 2.10 (m, 2H), 1.95 (d, J = 9.5 Hz,2H), 1.54 (s, 3H), 1.00 - 0.87 (m, 4H). [M+H] = 392.

Example 302.N-[1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.77 (s, 2H), 8.40 (s, 1H), 5.38 (q, J = 7.0Hz, 1H), 2.81 (s, 3H), 1.65 (d, J = 7.0 Hz, 3H), 1.52 (s, 3H), 0.97 -0.87 (m, 4H). [M+H] = 371.

Example 303.5-{2-Fluoro-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbony]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.52 (br s, 1H), 8.41 (s, 1H), 4.92 (br s,2H), 4.04 (br s, 2H), 3.12 - 3.05 (m, 2H), 2.59 (s, 3H), 1.48 (s, 3H),0.92 - 0.83 (m, 4H). [M+H] = 383.

Example 304.N-[1-(3-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.66 - 8.53 (m, 1H), 8.35 (s, 1H), 7.19 (t, J= 2.6 Hz, 1H), 7.16 (s, 1H), 7.11 - 7.04 (m, 1H), 5.23 - 5.11 (m, 1H),3.86 (s, 3H), 2.66 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H), 1.48 (s, 3H),0.93 - 0.80 (m, 4H). [M+H] = 399.1.

Example 305.N-[(1S)-1-(2-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.60 (d, J = 7.5 Hz, 1H), 8.36 (s, 1H), 7.21 -7.14 (m, 2H), 7.14 - 7.04 (m, 1H), 5.24 - 5.14 (m, 1H), 3.87 (s, 3H),2.68 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H), 1.49 (s, 3H), 0.96 - 0.83 (m,4H). [M+H] = 399.

Example 306.N(1R)-1-(2-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J = 7.1 Hz, 1H), 8.36 (s, 1H), 7.19(t, J = 2.6 Hz, 1H), 7.16 (s, 1H), 7.12 - 7.05 (m, 1H), 5.22 - 5.14 (m,1H), 3.87 (s, 3H), 2.67 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H), 1.49 (s, 3H),0.92 - 0.80 (m, 4H). [M+H] = 399.

Example 307.5-{2-Fluoro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.41 (s, 1H), 4.88 (br s, 2H),3.98 (br s, 2H), 2.99 (br s, 2H), 2.59 (s, 3H), 1.48 (s, 3H),. [M+H] =383.

Example 308.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(tetrachloropyridin-2-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 6.98 (s, 1H), 3.83 (br s, 4H),3.47 (br s, 4H), 2.52 (s, 3H), 1.55 (s, 3H), 0.85 (br s, 2H), 0.79 (brs, 2H). [M+H] = 531.1.

Example 309.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.77 (d, J = 4.9 Hz, 2H), 8.42 (s, 1H), 7.37(t, J = 5.0 Hz, 1H), 3.26 (tt, J = 3.8, 11.5 Hz, 2H), 2.59 (s, 3H),2.20 - 1.86 (m, 4H), 1.55 (s, 3H), 1.04 - 0.86 (m, 4H). [M+H] = 393.

Example 310.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(5,6,7,8-tetrahydroquinolin-8-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.60 (dd, J = 1.3, 5.4 Hz, 1H), 8.38 (s, 1H),8.24 (d, J = 7.3 Hz, 1H), 7.77 (dd, J = 5.5, 7.8 Hz, 1H), 5.62 - 5.46(m, 1H), 3.07 (d, J = 5.5 Hz, 2H), 2.71 (s, 3H), 2.43 - 2.26 (m, 1H),2.26 - 1.95 (m, 3H), 1.54 (s, 3H), 1.00 - 0.82 (m, 4H). [M+H] = 378.

Example 311.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.60 (d, J = 1.5 Hz, 1H), 8.56 (dd, J = 1.6,2.4 Hz, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.40 (s, 1H), 2.77 (s, 3H),1.81 - 1.71 (m, 2H), 1.58 - 1.44 (m, 5H), 0.95 - 0.79 (m, 4H). [M+H] =365.

Example 312.N(6-Chloropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J = 2.1 Hz, 1H), 8.38 - 8.34 (m, 1H),7.91 - 7.85 (m, 1H), 7.47 (d, J = 8.3 Hz, 1H), 4.62 (s, 2H), 2.70 (s,3H), 1.50 (s, 3H), 0.94 - 0.84 (m, 4H). [M+H] = 371.9.

Example 313.N-[(2-Chloropyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 2H), 8.37 (s, 1H), 4.62 (s, 2H), 2.72(s, 3H), 1.50 (s, 3H), 0.95 - 0.87 (m, 4H). [M+H] = 372.9.

Example 314.5-(3-Fluoro-3-phenylazetidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 - 8.36 (m, 1H), 7.56 - 7.51 (m, 2H),7.50 - 7.40 (m, 3H), 4.72 (s, 2H), 4.67 (s, 2H), 2.65 (s, 3H), 1.52 (s,3H), 0.99 - 0.85 (m, 4H). [M+H] = 381.1.

Example 315.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.75 (d, J = 1.5 Hz, 1H), 8.65 (dd, J = 1.5,2.5 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.41 - 8.34 (m, 1H), 5.40 (q, J =7.1 Hz, 1H), 2.82 - 2.71 (m, 3H), 1.67 (d, J = 7.0 Hz, 3H), 1.51 (s,3H), 0.97 - 0.81 (m, 4H). [M+H] = 353.

Example 316.N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 5.3 Hz, 1H), 8.40 (s, 1H), 8.12(d, J = 7.7 Hz, 1H), 7.61 (dd, J = 5.5, 7.6 Hz, 1H), 5.80 (t, J = 8.4Hz, 1H), 3.30 - 3.19 (m, 1H), 3.19 - 3.04 (m, 1H), 2.89 - 2.76 (m, 1H),2.74 (s, 3H), 2.26 (qd, J = 8.8, 13.0 Hz, 1H), 1.54 (s, 3H), 1.05 -0.86(m, 4H). [M+H] = 364.

Example 317.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-4-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.17 (d, J = 1.2 Hz, 1H), 8.78 (d, J = 5.3 Hz,1H), 8.40 (s, 1H), 7.62 (dd, J = 1.2, 5.3 Hz, 1H), 5.27 (q, J = 7.1 Hz,1H), 2.81 (s, 3H), 1.64 (d, J = 7.1 Hz, 3H), 1.51 (s, 3H), 1.01 - 0.80(m, 4H). [M+H] = 353.

Example 318.N-[(3-Bromo-1,2-oxazol-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.28 (s, 1H), 6.57 (s, 1H), 4.75(s, 2H), 2.68 (s, 3H), 1.50 (s, 3H), 0.87 - 0.70 (m, 4H). [M+H] = 405.8.

Example 319.6-Methyl-N-[(3-methyl-1,2-oxazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 6.26 (s, 1H), 4.70 (s, 2H), 2.67(s, 3H), 2.29 (s, 3H), 1.50 (s, 3H), 0.88 - 0.69 (m, 4H). [M+H] = 342.0.

Example 320.6-Methyl-5-[3-(1-methyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.54 (d, J = 1.7 Hz, 2H), 4.31 -3.71 (m, 8H), 2.60 (s, 4H), 2.32 (br s, 1H), 1.58 - 1.48 (m, 3H), 0.99 -0.81 (m, 4H). [M+H] = 381.

Example 321.6-Methyl-5-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.65 - 7.31 (m, 2H), 4.07 - 3.36(m, 8H), 2.57 (s, 3H), 2.49 - 2.27 (m, 1H), 2.21 - 1.96 (m, 1H), 1.58 -1.46 (m, 3H), 1.02 - 0.85 (m, 4H). [M+H] = 381.

Example 322.N-[(5-Ethyl-1,2-oxazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 6.20 (s, 1H), 4.65 (s, 2H),2.86 - 2.76 (m, 2H), 2.74 (s, 3H), 1.57 - 1.47 (m, 3H), 1.31 (t, J = 7.6Hz, 3H), 1.02 - 0.87 (m, 4H). [M+H] = 356.

Example 323.N[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 6.12 (s, 1H), 4.62 (s, 2H), 2.73(s, 3H), 2.12 (tt, J = 5.0, 8.5 Hz, 1H), 1.54 (s, 3H), 1.17 - 1.03 (m,2H), 1.03 - 0.86 (m, 6H). [M+H] = 368.

Example 324.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,2-oxazol-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 6.19 (d, J = 0.6 Hz, 1H), 4.65(s, 2H), 3.19 -3.03 (m, 1H), 2.79 - 2.67 (m, 3H), 1.53 (s, 3H), 1.33 (d,J = 7.0 Hz, 6H), 1.02 - 0.85 (m, 4H). [M+H] = 370.

Example 325.N-{[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.95 - 7.84 (m, 2H), 7.34 - 7.21(m, 2H), 6.81 (s, 1H), 4.74 (s, 2H), 2.76 (s, 3H), 1.58 - 1.47 (m, 3H),1.01 - 0.84 (m, 4H). [M+H] = 422.

Example 326.N-{[5-(4-Methoxyphenyl)-1,2-oxazol-3-yl]methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.06(d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 4.71 (s, 2H), 3.87 (s, 3H), 2.75 (s,3H), 1.52 (s, 3H), 0.99 - 0.80 (m, 4H). [M+H] = 434.

Example 327.5-[4-(5-Methoxypyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.19 (s, 2H), 4.00 - 3.67 (m,11H), 2.58 (s, 3H), 1.53 (s, 3H), 1.00 - 0.84 (m, 4H). [M+H] = 424.

Example 328.3-[({6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-yl}formamido)methyl]-1,2-oxazole-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 6.71 (s, 1H), 4.80 (s, 2H), 2.75(s, 3H), 1.53 (s, 3H), 1.03 - 0.86 (m, 4H). [M+H] = 370.9.

Example 329.2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-5-ol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.67(d, J = 7.9 Hz, 1H), 6.63 (d, J = 6.4 Hz, 1H), 4.78 (br s, 2H), 3.93 (brs, 2H), 2.87 (t, J = 5.7 Hz, 2H), 2.53 (s, 3H), 1.47 (s, 3H), 0.88 -0.81 (m, 4H). [M+H] = 379.

Example 330.2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-ol

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 6.96 (br s, 1H), 6.70 - 6.61 (m,2H), 4.72 (br s, 2H), 3.90 (br s, 2H), 2.91 (br s, 2H), 2.54 (s, 3H),1.47 (s, 3H), 0.85 (d, J = 4.0 Hz, 4H). [M+H] = 379.

Example 331.2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-8-ol

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.66(dd, J = 7.8, 17.2 Hz, 2H), 4.71 (br s, 2H), 3.93 (br s, 2H), 2.94 (brs, 2H), 2.54 (s, 3H), 1.47 (s, 3H), 0.91 -0.81 (m, 4H). [M+H] = 379.

Example 332.2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-7-ol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.65(dd, J = 2.5, 8.3 Hz, 1H), 6.57 (br s, 1H), 4.73 (br s, 2H), 3.88 (br s,2H), 2.87 (br s, 2H), 2.53 (s, 3H), 1.46 (s, 3H), 0.85 (d, J = 4.3 Hz,4H). [M+H] = 379.

Example 333.6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2.3-d]pyrimidine-5-carbonyl}-5,6,7,8-tetrahydro-1,6-naphthyridin-3-ol

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 7.73(br s, 1H), 4.98 (br s, 2H), 4.42 - 3.79 (m, 2H), 3.20 - 3.13 (m, 2H),2.57 (s, 3H), 1.52 - 1.44 (m, 3H), 0.85 -0.76 (m, 4H). [M+H] = 378.

Example 334.5-[4-(3-Chloro-5-fluoropyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J = 2.3 Hz, 1H), 8.33 (s, 1H), 7.76(dd, J = 2.6, 8.3 Hz, 1H), 4.78 - 3.85 (m, 2H), 3.60 (br s, 2H), 3.43 -2.93 (m, 3H), 2.54 (s, 3H), 1.93 (br s, 4H), 1.53 (s, 3H), 0.89 (br s,2H), 0.81 (br s, 2H). [M+H] = 444.

Example 335.5-[3-(5-Chloropyrimidin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.93 - 8.55 (m, 2H), 8.31 (s, 1H), 4.19 - 3.60(m, 6H), 2.55 (s, 4H), 2.43 (br s, 2H), 1.51 (s, 4H), 0.91 - 0.67 (m,5H). [M+H] = 412.9.

Example 336.N-[(4-Fluoro-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.71 (br s, 1H), 8.33 (s, 1H), 7.14 (dd, J =2.0, 8.1 Hz, 1H), 7.06 (dd, J = 8.3, 11.3 Hz, 1H), 6.93 (ddd, J = 2.1,4.2, 8.3 Hz, 1H), 4.59 - 4.52 (m, 2H), 3.88 (s, 3H), 2.67 (s, 3H), 1.50(s, 3H), 0.93 - 0.81 (m, 4H). [M+H] = 385.

Example 337.6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,5,6,7,8-hexahydro-2,6-naphthyridin-1-one

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.30 (d, J = 6.6 Hz, 1H), 6.26(d, J = 5.3 Hz, 1H), 4.71 (br s, 2H), 3.91 (br s, 2H), 2.70 (br s, 2H),2.57 (s, 3H), 1.48 (s, 3H), 0.93 - 0.85 (m, 4H). [M+H] = 380.

Example 338.1-Methyl-2-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-7-ol

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.67(dd, J = 2.3, 8.3 Hz, 2H), 6.08 - 4.87 (m, 1H), 3.05 - 2.73 (m, 2H),2.50 (br s, 4H), 1.70 - 1.27 (m, 7H), 0.82 (br s, 4H). [M+H] = 393.1.

Example 339.5-[3-(5-Fluoropyridin-3-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.67(dd, J = 2.3, 8.3 Hz, 2H), 6.10 - 5.04 (m, 1H), 4.82 - 3.35 (m, 2H),3.08 - 2.70 (m, 2H), 2.50 (br s, 3H), 1.54 (br s, 3H), 1.45 (br s, 3H),0.81 (br s, 4H). [M+H] = 393.

Example 340.N-[(4-Fluoro-3-nitrophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.53 - 8.29 (m, 3H), 7.86 - 7.62 (m, 1H),4.26 - 3.98 (m, 1H), 3.96 - 3.54 (m, 4H), 2.61 (d, J = 10.8 Hz, 3H),2.56 - 2.37 (m, 1H), 2.35 - 2.11 (m, 1H), 1.54 (s, 3H), 1.04 - 0.83 (m,4H). [M+H] = 396.0.

Example 341.N-[(4-Cyano-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.17 (dd, J = 2.2, 7.1 Hz, 1H),7.79 (ddd, J = 2.4, 4.2, 8.6 Hz, 1H), 7.45 (dd, J = 8.6, 10.9 Hz, 1H),4.73 - 4.57 (m, 2H), 2.73 (s, 3H), 1.52 (s, 3H), 1.01 - 0.79 (m, 4H).[M+H] = 400.0.

Example 342.5-[4-(Cyclopropylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.44 - 8.32 (m, 1H), 3.99 (br s,2H), 3.24 -3.11 (m, 1H), 2.66 (br s, 2H), 2.63 - 2.54 (m, 3H), 1.49 (s,3H), 1.02 - 0.92 (m, 2H), 0.89 - 0.74 (m, 6H). [M+H] = 420.

Example 343.5-{4-[(Cyclopropylmethyl)amino]-5H,6H,7H,8H-pyridor[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furor[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 8.36 (s, 1H), 4.34 - 3.73 (m,2H), 3.55 (d, J = 7.1 Hz, 2H), 2.70 (br s, 2H), 2.59 (s, 3H), 1.49 (s,3H), 1.27 - 1.14 (m, 1H), 0.87 - 0.74 (m, 4H), 0.63 - 0.52 (m, 2H),0.41 - 0.31 (m, 2H). [M+H] = 434.1.

Example 344.5-[4-(5-Chloropyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.78 (s, 2H), 8.41 (s, 1H), 3.30 - 3.21 (m,1H), 2.57 (s, 3H), 2.14 (d, J = 11.0 Hz, 2H), 1.92 (br s, 2H), 1.54 (s,3H), 1.02 - 0.93 (m, 2H), 0.93 - 0.85 (m, 2H). [M+H] = 427.

Example 345.5-[4-(4-Methoxypyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, J = 6.4 Hz, 1H), 8.42 (s, 1H), 6.92(d, J = 6.2 Hz, 1H), 4.09 (s, 3H), 3.25 (tt, J = 3.8, 11.4 Hz, 1H), 2.59(s, 3H), 2.16 (d, J = 12.0 Hz, 2H), 1.98 (br s, 2H), 1.54 (s, 3H),1.02 - 0.87 (m, 4H). [M+H] = 423.

Example 346.4-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}pyrrolidin-3-yl)phenol

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.24 - 7.03 (m, 2H), 6.83 - 6.69(m, 2H), 4.06 - 3.36 (m, 5H), 2.57 (d, J = 15.2 Hz, 3H), 2.44 - 2.24 (m,1H), 2.22 - 1.99 (m, 1H), 1.52 (s, 3H), 1.02 - 0.87 (m, 4H). [M+H] =393.

Example 347.1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furor[2,3-d]pyrimidine-5-carbonyl}-3-phenylpyrrolidin-3-ol

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.67 - 7.46 (m, 2H), 7.45 - 7.24(m, 3H), 4.22 - 3.65 (m, 4H), 2.68 - 2.40 (m, 4H), 2.36 - 2.17 (m, 1H),1.51 (s, 3H), 1.02 - 0.83 (m, 4H). [M+H] = 393.

Example 348.5-[3-(5-Chloropyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.65 - 8.40 (m, 1H), 8.36 (s, 1H), 7.88 - 7.71(m, 1H), 7.48 - 7.29 (m, 1H), 4.10 - 3.54 (m, 5H), 2.63 - 2.53 (m, 3H),2.51 - 2.11 (m, 2H), 1.52 (s, 3H), 0.98 - 0.84 (m, 4H). [M+H] = 412.

Example 349.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.72 (d, J = 4.9 Hz, 2H), 8.42 (s, 1H), 7.30(t, J = 4.9 Hz, 1H), 2.74 (s, 3H), 1.85 - 1.77 (m, 2H), 1.57 - 1.46 (m,5H), 0.94 - 0.83 (m, 4H). [M+H] = 365.

Example 350.6-Methyl-N-(5-methyl-1,2-oxazol-3-yl)ethyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 6.21 (d, J = 0.7 Hz, 1H), 5.36(q, J = 7.1 Hz, 1H), 2.73 (s, 3H), 2.44 (d, J = 0.7 Hz, 3H), 1.63 (d, J= 7.1 Hz, 3H), 1.53 (s, 3H), 1.04 - 0.84 (m, 4H). [M+H] = 356.

Example 351.5-[4-(2-Chloro-5-fluoropyrimidin-4-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J = 1.7 Hz, 1H), 8.42 (s, 1H), 3.55 -3.45 (m, 1H), 3.33 (td, J = 1.7, 3.2 Hz, 24H), 2.58 (s, 3H), 2.05 - 1.77(m, 4H), 1.55 (s, 3H), 1.06 - 0.87 (m, 4H). [M+H] = 445.0.

Example 352.6-Methyl-N-{[5-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 6.53(s, 1H), 4.70 (s, 2H), 3.97 (s, 3H), 2.75 (s, 3H), 1.53 (s, 3H), 0.99 -0.84 (m, 4H). [M+H] = 408.

Example 353.N-[1-(Hydroxymethyl)cyclobutyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.09 (s, 1H), 3.86 (s, 2H), 2.67(s, 3H), 2.40 - 2.30 (m, 2H), 2.29 - 2.20 (m, 2H), 2.05 - 1.81 (m, 2H),1.48 (s, 3H), 0.93 - 0.81 (m, 4H). [M+H] = 331.

Example 354.5-[3-(6-Fluoropyridin-2-yl)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furor2,3-d-]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.89 (q, J = 8.2 Hz, 1H), 7.24(dd, J = 2.3, 7.3 Hz, 1H), 6.97 (dd, J = 2.3, 8.2 Hz, 1H), 4.61 (t, J =9.0 Hz, 2H), 4.39 (br s, 2H), 4.09 (tt, J = 5.8, 8.7 Hz, 1H), 2.65 (s,3H), 1.54 (s, 3H), 1.05 - 0.88 (m, 4H). [M+H] = 382.

Example 355.2-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)pyrimidin-5-ol

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.31 (s, 2H), 3.18 (tt, J = 3.8,11.5 Hz, 1H), 2.59 (s, 3H), 2.16 - 2.02 (m, 2H), 1.90 (br s, 2H), 1.55(s, 3H), 1.04 - 0.89 (m, 4H). [M+H] = 409.1.

Example 356.5-[4-(5-Fluoropyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 2H), 8.42 (s, 1H), 3.31 - 3.24 (m,1H), 2.58 (s, 3H), 2.24 - 2.04 (m, 2H), 1.93 (br s, 2H), 1.54 (s, 3H),1.04 - 0.86 (m, 4H). [M+H] = 411.1.

Example 357.5-[4-(5-Fluoropyrimidin-2-yl)-2-methylpiperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.33 (s, 2H), 5.03 (br s, 1H),4.52 (d, J = 12.2 Hz, 2H), 4.29 - 3.57 (m, 2H), 3.54 - 3.02 (m, 21H),2.55 (s, 3H), 1.51 (s, 3H), 1.37 - 0.89 (m, 4H), 0.85 (s, 3H). [M+H] =426.

Example 358.5-[4-(5-Fluoropyrimidin-2-yl)-3-methylpiperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 8.33 (s, 2H), 4.81 - 4.50 (m,3H), 3.98 (br s, 1H), 3.74 - 3.47 (m, 1H), 3.36 (br s, 1H), 3.19 - 2.97(m, 1H), 2.57 (s, 3H), 1.52 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H), 0.99 -0.81 (m, 4H). [M+H] = 426.1.

Example 359.5-[4-(2-Fluoro-4-methanesulfonylphenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.77 - 7.59 (m, 2H), 7.26 (t, J= 8.4 Hz, 1H), 3.91 (br s, 4H), 3.35 (d, J = 1.6 Hz, 3H), 3.12 (s, 3H),2.60 (s, 3H), 1.54 (s, 3H), 1.00 - 0.85 (m, 4H). [M+H] = 487.9.

Example 360.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(5-methylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (s, 2H), 8.40 (s, 1H), 3.22 (tt, J = 4.0,11.6 Hz, 1H), 2.57 (s, 3H), 2.33 (s, 3H), 2.17 - 2.03 (m, 2H), 1.92 (brs, 2H), 1.54 (s, 3H), 1.02 - 0.93 (m, 2H), 0.93 - 0.84 (m, 2H). [M+H] =407.1.

Example 361.5-[3-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.24 (td, J = 7.5, 15.2 Hz, 1H),6.98 - 6.88 (m, 1H), 6.88 - 6.75 (m, 2H), 4.11 - 3.88 (m, 1H), 3.87 -3.72 (m, 5H), 3.69 - 3.36 (m, 2H), 2.58 (d, J = 13.9 Hz, 3H), 2.52 -2.02 (m, 2H), 1.53 (s, 3H), 1.00 - 0.86 (m, 4H). [M+H] = 407.09.

Example 362.5-[4-(2-Chloro-5-fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.08 (d, J = 6.4 Hz, 1H), 7.28(s, 1H), 4.07 -3.68 (m, 8H), 2.54 (s, 3H), 1.51 (s, 3H), 0.92 - 0.69 (m,4H). [M+H] = 446.0.

Example 363.N′-(5-Fluoropyrimidin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbohydrazide

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 3H), 2.81 (s, 3H), 1.54 (s, 3H),1.06 - 0.83 (m, 4H). [M+H] = 358.0.

Example 364.5-[4-(6-Methoxypyridazin-3-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.16(d, J = 9.0 Hz, 1H), 4.08 (s, 3H), 3.73 - 2.96 (m, 7H), 2.54 (s, 3H),2.15 - 2.04 (m, 2H), 2.07 (br s, 2H), 1.98 - 1.74 (m, 2H), 1.52 (s, 3H),0.93 - 0.69 (m, 4H). [M+H] = 423.1.

Example 365.5-[4-(5-Methoxypyrazin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 4.59(br s, 3H), 3.96 (s, 3H), 3.29 - 2.97 (m, 3H), 2.53 (br s, 3H), 2.16 -1.68 (m, 4H), 1.53 (s, 3H), 0.96 - 0.70 (m, 4H). [M+H] = 423.0.

Example 366.5-[4-(5-Methoxypyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.42 -7.33 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 4.79 - 3.98 (m, 2H), 3.87 (s,3H), 3.23 - 2.85 (m, 2H), 2.54 (br s, 3H), 2.15 - 1.64 (m, 4H), 1.52 (s,3H), 0.98 - 0.62 (m, 4H). [M+H] = 422.1.

Example 367.5-[3-(6-Methoxypyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amirie

¹H NMR (400 MHz, CD₃OD) δ 8.36 (br s, 1H), 7.72 - 7.48 (m, 1H), 7.00 -6.80 (m, 1H), 6.70 - 6.58 (m, 1H), 4.05 - 3.76 (m, 7H), 3.72 - 3.50 (m,1H), 2.56 (br s, 3H), 2.46 - 2.20 (m, 2H), 1.50 (s, 3H), 0.86 (s, 4H).[M+H] = 408.03.

Example 368.5-[4-(4-Cyclopropylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 5.6 Hz, 1H), 8.45 (s, 1H), 7.36(d, J = 5.5 Hz, 1H), 3.21 (tt, J = 3.7, 11.4 Hz, 1H), 2.63 - 2.56 (m,3H), 2.19 (quin, J = 6.3 Hz, 1H), 2.10 (d, J = 11.4 Hz, 2H), 1.92 (br s,2H), 1.55 (s, 3H), 1.30 - 1.17 (m, 4H), 1.06 - 0.91 (m, 4H). [M+H] =433.03.

Example 369.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-propylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (d, J = 5.3 Hz, 1H), 8.41 (s, 1H), 7.25(d, J = 5.1 Hz, 1H), 3.23 (tt, J = 3.8, 11.4 Hz, 2H), 2.83 - 2.72 (m,2H), 2.58 (s, 3H), 2.08 (br s, 2H), 1.96 (br s, 2H), 1.79 (sxt, J = 7.5Hz, 2H), 1.61 - 1.49 (m, 3H), 1.05 - 0.85 (m, 7H). [M+H] = 435.04.

Example 370.5-[4-(5-Methoxypyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 2H), 8.40 (s, 1H), 3.95 (s, 3H), 3.21(tt, J = 3.8, 11.5 Hz, 1H), 2.57 (s, 3H), 2.08 (br s, 2H), 1.91 (br s,2H), 1.54 (s, 3H), 1.01 - 0.85 (m, 4H). [M+H] = 423.05.

Example 371.N-{1-[(4-Methoxyphenyl)methyl]cyclopropyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.28 (s, 1H), 7.18 (d, J = 8.6Hz, 2H), 6.87 -6.82 (m, 2H), 3.75 (s, 3H), 2.98 (s, 2H), 2.32 - 2.28 (m,3H), 1.54 (s, 3H), 1.02 - 0.89 (m, 8H). [M+H] = 407.04.

Example 372.5-[3-(6-Bromopyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.63 (dd, J = 8.1, 12.7 Hz, 1H),7.52 - 7.27 (m, 2H), 4.09 - 3.56 (m, 5H), 2.59 (d, J = 7.7 Hz, 3H),2.50 - 2.12 (m, 2H), 1.51 (s, 3H), 0.99 -0.80 (m, 4H). [M+H] = 458.10.

Example 373.5-[3-(5-Bromopyridin-2-yl)pyrrolidine-1-carbony1]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.71 - 8.46 (m, 1H), 8.36 (s, 1H), 8.01 - 7.84(m, 1H), 7.43 - 7.23 (m, 1H), 4.08 - 3.88 (m, 2H), 3.86 - 3.53 (m, 3H),2.56 (br s, 3H), 2.51 - 2.13 (m, 2H), 1.52 (s, 3H), 0.96 - 0.80 (m, 4H).[M+H] = 458.10.

Example 374.N-(1-Fluoro-2-methylpropan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.85 (br s, 1H), 4.69 - 4.50 (m,2H), 2.67 (s, 3H), 1.52 (s, 3H), 1.47 (d, J = 2.0 Hz, 6H), 0.96 - 0.87(m, 4H). [M+H] = 321.20.

Example 375.1′-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3′-piperidine]-2-one

¹H NMR (400 MHz, CD₃OD) δ 8.52 - 8.25 (m, 1H), 7.46 - 6.74 (m, 5H), 4.63(br s, 1H), 4.18 - 3.38 (m, 4H), 2.55 (br s, 2H), 2.42 (s, 2H), 2.29 -1.90 (m, 3H), 1.69 (br s, 1H), 1.61 (br s, 2H), 1.57 (s, 2H), 1.22 (brs, 1H), 1.14 - 0.82 (m, 4H). [M+H] = 432.3.

Example 376.1-Methyl-1′-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3′-piperidine]-2-one

¹H NMR (400 MHz, CD₃OD) δ 8.59 - 8.21 (m, 1H), 7.66 - 6.82 (m, 5H), 4.57(br s, 1H), 4.10 (br s, 1H), 3.97 - 3.70 (m, 1H), 3.69 - 3.57 (m, 1H),3.39 (d, J = 19.2 Hz, 1H), 2.97 (br s, 1H), 2.54 (br s, 2H), 2.40 (s,2H), 2.20 (br s, 1H), 1.91 (d, J = 12.3 Hz, 1H), 1.74 - 1.51 (m, 5H),1.36 - 1.16 (m, 1H), 1.13 - 0.85 (m, 4H). [M+H] = 446.3.

Example 377.1′-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-2-oxo-1,2-dihydrospirorindole-3,3′-pyrrolidine]-4′-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (br s, 1H), 8.33 (br s, 1H), 7.47 -6.82 (m, 5H), 4.44 - 3.71 (m, 11H), 2.59 (br s, 1H), 2.45 (br s, 2H),1.49 (s, 3H), 0.80 (d, J = 5.7 Hz, 4H). [M+H] = 443.3.

Example 378.5-({2,3-Dihydrospirorindene-1,2′-morpholine]-4′-yl}carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.29(br s, 3H), 4.33 (br s, 1H), 3.87 (br s, 4H), 3.04 (br s, 2H), 2.55 (brs, 4H), 2.14 (br s, 1H), 1.56 (s, 3H), 1.03 - 0.81 (m, 4H). [M+H] =419.3.

Example 379.6-Methyl-N-O-methylcyclopropyl)-5-({3H-spiro[2-benzofuran-1,3′-piperidine]-1′-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.56 - 6.94 (m, 4H), 5.23 (br s,1H), 4.84 -4.38 (m, 1H), 4.33 - 3.75 (m, 1H), 3.73 - 3.37 (m, 2H),3.26 - 3.00 (m, 1H), 2.42 (br s, 3H), 2.16 (br s, 2H), 2.01 - 1.67 (m,2H), 1.58 (s, 3H), 1.13 - 0.81 (m, 4H). [M+H] = 419.3.

Example 380.6-Methyl-N-(1-methylcyclopropyl)-5-({3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (br s, 1H), 7.45 - 7.23 (m, 4H), 5.32 -4.97 (m, 2H), 4.22 - 3.70 (m, 4H), 2.60 (d, J = 19.8 Hz, 3H), 2.47 (d, J= 10.1 Hz, 1H), 2.37 - 2.17 (m, 1H), 1.55 (s, 3H), 1.09 - 0.84 (m, 4H).[M+H] = 405.3.

Example 381.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyrimidin-5-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.56 (s, 2H), 8.43 (s, 1H), 3.91(br s, 4H), 3.47 (br s, 4H), 2.60 (s, 3H), 1.53 (s, 3H), 0.99 - 0.86 (m,4H). [M+H] = 394.08.

Example 382.4-(1-(6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)benzamide

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.39(d, J = 8.2 Hz, 2H), 3.01 (t, J = 12.1 Hz, 1H), 2.59 (s, 3H), 2.12 -1.92 (m, 2H), 1.92 - 1.65 (m, 2H), 1.55 (s, 3H), 1.04 - 0.88 (m, 4H).[M+H] = 434.11.

Example 383.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(6-methylpyridin-3-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.64 (s, 1H), 8.48 (dd, J = 1.7, 8.4 Hz, 1H),8.39 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 3.21 (t, J = 12.2 Hz, 1H),2.84 - 2.72 (m, 3H), 2.59 (s, 3H), 2.17 - 1.95 (m, 2H), 1.84 (d, J =10.3 Hz, 2H), 1.54 (s, 3H), 1.00 - 0.83 (m, 4H). [M+H] = 406.10.

Example 384.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-methylphenyl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.17 - 7.07 (m, 4H), 2.94 - 2.80(m, 1H), 2.56 (s, 3H), 2.35 - 2.27 (m, 3H), 1.95 (d, J = 11.4 Hz, 2H),1.70 (br s, 2H), 1.54 (s, 3H), 1.01 -0.82 (m, 4H). [M+H] = 405.13.

Example 385.4-(1-(6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyllpiperidin-4-yl)benzonitrile.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.49(d, J = 8.2 Hz, 2H), 3.04 (t, J = 12.0 Hz, 1H), 2.58 (s, 3H), 2.12 -1.90 (m, 2H), 1.90 - 1.65 (m, 2H), 1.54 (s, 3H), 1.01 - 0.83 (m, 4H).[M+H] = 416.10.

Example 386.6-Fluoro-1′-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidinel]-2-one.

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.14 (d, J = 8.9 Hz, 1H), 7.11 -7.04 (m, 1H), 6.94 (dd, J = 4.6, 8.8 Hz, 1H), 4.63 (br s, 1H), 4.76 -3.39 (m, 4H), 2.61 (s, 3H), 2.33 - 2.08 (m, 4H), 1.55 (s, 3H), 1.07 -0.83 (m, 4H). [M+H] = 466.0.

Example 387.6-Methyl-N-(1-methylcyclopropyl)-5-({spiro[indene-1,4′-piperidine]-1′-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine,

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.38 (br s, 1H), 7.34 (s, 1H),7.29 - 7.16 (m, 2H), 7.08 (d, J = 4.9 Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H),4.77 - 3.42 (m, 4H), 2.63 (s, 3H), 2.16 (br s, 2H), 1.58 (s, 3H), 1.45(d, J = 11.4 Hz, 2H), 1.10 - 0.86 (m, 4H). [M+H] = 415.1.

Example 388.6-Methyl-N-(1-methylcyclopropyl)-5-({3H-spiro[2-benzothiophene-1,4′-piperidine]-1′-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.38 - 7.15 (m, 4H), 4.78 - 4.34(m, 1H), 4.24 (s, 2H), 4.19 - 3.38 (m, 2H), 3.27 - 3.07 (m, 1H), 2.59(s, 3H), 2.26 (br s, 2H), 2.00 (d, J = 11.7 Hz, 2H), 1.56 (s, 3H),1.02 - 0.83 (m, 4H). [M+H] = 435.1.

Example 389.5-[3-(3-Fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.35 (d, J = 15.8 Hz, 1H),7.25 - 6.88 (m, 3H), 4.11 - 3.90 (m, 1H), 3.88 - 3.44 (m, 4H), 2.57 (d,J = 11.0 Hz, 3H), 2.50 - 1.98 (m, 2H), 1.51 (s, 3H), 0.97 - 0.82 (m,4H). [M+H] = 395.08.

Example 390.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-methylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, J = 5.3 Hz, 1H), 8.52 - 8.41 (m, 1H),7.31 (d, J = 5.3 Hz, 1H), 3.23 (tt, J = 3.7, 11.5 Hz, 1H), 2.61 (s, 3H),2.57 (s, 3H), 2.18 - 2.04 (m, 2H), 1.98 (br s, 2H), 1.59 - 1.53 (m, 3H),1.08 - 0.92 (m, 4H). [M+H] = 407.12.

Example 391.5-[4-(4,5-Dimethylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.44 (s, 1H), 3.27 - 3.17 (m,1H), 2.57 (d, J = 15.9 Hz, 6H), 2.32 (s, 3H), 2.08 (d, J = 10.3 Hz, 2H),1.96 (br s, 2H), 1.58 - 1.52 (m, 3H), 1.07 - 0.88 (m, 4H). [M+H] =421.13.

Example 392.1′-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3′-pyrrolidine]-2-one.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J = 18.5 Hz, 1H), 7.49 - 6.76 (m,5H), 4.40 -3.83 (m, 4H), 2.76 - 2.52 (m, 3H), 2.51 - 2.26 (m, 2H), 1.58(s, 3H), 1.22 - 0.84 (m, 4H). [M+H] = 418.1.

Example 393.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(5-methylpyrazin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.45 (s, 1H), 8.43 (s, 1H), 3.17(ddd, J = 3.6, 8.1, 11.7 Hz, 1H), 2.63 - 2.57 (m, 3H), 2.55 (s, 3H),2.01 (br s, 2H), 1.91 (br s, 2H), 1.55 (s, 3H), 1.04 - 0.97 (m, 2H),0.97 - 0.90 (m, 2H). [M+H] = 407.08.

Example 394.5-[4-(2-Methoxypyrimidin-5-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 2H), 8.46 (s, 1H), 4.08 - 3.95 (m,3H), 3.04 -2.92 (m, 1H), 2.61 (s, 3H), 2.01 (d, J = 12.0 Hz, 2H), 1.89 -1.69 (m, 2H), 1.56 (s, 3H), 1.09 -0.91 (m, 4H). [M+H] = 423.10.

Example 395.6-Methyl-N-(1-methylcyclopropyl)-5-[3-(3-methylphenyl)pyrrolidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.30 - 6.99 (m, 4H), 4.12 - 3.37(m, 5H), 2.59 (d, J = 15.7 Hz, 3H), 2.48 - 2.02 (m, 5H), 1.54 (s, 3H),1.02 - 0.84 (m, 4H). [M+H] = 391.09.

Example 396.6-Methyl-N-(1-methylcyclopropyl)-5-{3-[3-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.75 - 7.47 (m, 4H), 4.20 - 3.50(m, 5H), 2.59 (d, J = 13.1 Hz, 3H), 2.54 - 2.08 (m, 2H), 1.53 (s, 3H),1.00 - 0.83 (m, 4H). [M+H] = 445.05.

Example 397.5-[3-(3,5-Dimethylphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.04 - 6.83 (m, 3H), 4.14 - 3.35(m, 5H), 2.58 (d, J = 15.0 Hz, 3H), 2.48 - 2.01 (m, 8H), 1.53 (s, 3H),1.02 - 0.83 (m, 4H). [M+H] = 405.11.

Example 398.5-[3-(3-Fluorophenoxy)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.39 - 7.11 (m, 1H), 6.70 (br s,3H), 5.23 -4.98 (m, 1H), 4.10 - 3.61 (m, 4H), 2.55 (br s, 3H), 2.28 (brs, 2H), 1.51 (s, 3H), 0.87 (d, J = 16.5 Hz, 4H). [M+H] = 411.06.

Example 399.5-[3-(4-Fluorophenoxy)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.14 - 6.78 (m, 4H), 5.18 - 4.92(m, 1H), 4.09 - 3.64 (m, 4H), 2.56 (br s, 3H), 2.27 (br s, 2H), 1.51 (s,3H), 0.95 - 0.81 (m, 4H). [M+H] = 411.07.

Example 400.N-(1-Cyclopropylethyl)-6-methyl-4-r(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 3.57 -3.43 (m, 1H), 2.69 (s, 3H), 1.51 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H),1.10 - 0.99 (m, 1H), 0.95 - 0.83 (m, 4H), 0.65 - 0.47 (m, 2H), 0.45 -0.26 (m, 2H). [M+H] = 315.06.

Example 401.N-(1-Cyclopropylpropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 3.40 -3.34 (m, 1H), 2.71 (s, 3H), 1.91 - 1.68 (m, 2H), 1.53 (s, 3H), 1.10 -0.96 (m, 4H), 0.95 - 0.86 (m, 4H), 0.72 - 0.61 (m, 1H), 0.58 - 0.47 (m,1H), 0.44 - 0.33 (m, 2H). [M+H] = 329.05.

Example 402.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1-methylcyclopropyl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 3.82 -3.69 (m, 1H), 2.70 (s, 3H), 1.51 (s, 3H), 1.28 (d, J = 7.0 Hz, 3H), 1.14(s, 3H), 0.99 - 0.87 (m, 4H), 0.70 -0.62 (m, 1H), 0.55 - 0.46 (m, 1H),0.42 - 0.29 (m, 2H). [M+H] = 329.05.

Example 403.5-{10-Azatricyclo[6.3.1.0²,7]dodeca-2,4,6-triene-10-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.52 - 6.97 (m, 4H), 4.73 (br s,1H), 3.81 (br s, 2H), 3.16 (br s, 2H), 2.58 - 2.41 (m, 1H), 2.37 (dd, J= 5.1, 10.3 Hz, 2H), 2.14 (d, J = 10.5 Hz, 1H), 1.47 (s, 3H), 0.77 (brs, 4H). [M+H] = 389.1.

Example 404.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yl)-1H-pyrazole-1-carbonyl]furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H),3.01 - 2.91 (m, 1H), 2.49 (s, 3H), 1.52 - 1.47 (m, 3H), 1.31 (d, J = 6.8Hz, 6H), 0.88 - 0.80 (m, 4H). [M+H] = 340.06.

Example 405.6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenyl-1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.73(d, J = 7.6 Hz, 2H), 7.50 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 2.55 (s,3H), 1.50 (s, 3H), 0.91 - 0.79 (m, 4H). [M+H] = 374.05.

Example 406.5-[4-(4-Methoxyphenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.64(d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 2.54 (s,3H), 1.50 (s, 3H), 0.92 - 0.79 (m, 4H). [M+H] = 404.06.

Example 407.5-[4-(4-Fluorophenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J = 2.9 Hz, 1H), 8.45 (s, 1H), 7.95 -7.88 (m, 2H), 7.23 - 7.15 (m, 2H), 7.13 (d, J = 2.9 Hz, 1H), 2.60 (s,3H), 1.44 (s, 3H), 0.84 - 0.75 (m, 4H). [M+H] = 392.05.

Example 408.6-Methyl-5-(4-methyl-1H-pyrazole-1-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 2.49(s, 3H), 2.18 (s, 3H), 1.49 (s, 3H), 0.91 - 0.82 (m, 4H). [M+H] =312.03.

Example 409.6-Methyl-N-(1-methylcyclopropyl)-5-(trimethyl-1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 2.56 (s, 3H), 2.39 (s, 3H), 2.19(s, 3H), 2.02 (s, 3H), 1.49 (s, 3H), 0.83 (s, 4H). [M+H] = 340.06.

Example 410.6-Methyl-N-(1-methylcyclopropyl)-5-(1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 2.9 Hz, 1H), 8.44 (s, 1H), 7.91(d, J = 1.2 Hz, 1H), 6.72 (dd, J = 1.5, 2.8 Hz, 1H), 2.51 (s, 3H), 1.51(s, 3H), 0.91 - 0.83 (m, 4H). [M+H] = 298.05.

Example 411.5-(3,5-Dimethyl-1H-pyrazole-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 6.27 (s, 1H), 2.63 (s, 3H),2.42 - 2.40 (m, 3H), 2.26 - 2.17 (m, 3H), 1.49 (s, 3H), 0.85 (s, 4H).[M+H] = 326.05.

Example 412.5-[4-(3-Methoxyphenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.83 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H),7.38 - 7.31 (m, 1H), 7.31 - 7.24 (m, 2H), 6.92 (dd, J = 1.9, 8.0 Hz,1H), 3.86 (s, 3H), 2.53 (s, 3H), 1.50 (s, 3H), 0.92 - 0.76 (m, 4H).[M+H] = 404.05.

Example 413.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1-methylcyclopropyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.31 (br s, 1H), 2.74 (s, 3H),1.52 (s, 3H), 1.16 (s, 4H), 1.05 - 0.93 (m, 5H), 0.58 - 0.54 (m, 2H),0.41 - 0.36 (m, 2H). [M+H] = 315.07.

Example 414.5-{3-[(4-Fluorophenyl)methyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.42 - 8.37 (m, 1H), 7.38 - 7.12 (m, 2H),7.10 - 6.89 (m, 2H), 3.89 - 3.52 (m, 3H), 3.47 - 3.34 (m, 1H), 3.47 -3.34 (m, 1H), 2.93 - 2.58 (m, 3H), 2.54 (d, J = 5.3 Hz, 3H), 2.20 - 1.96(m, 1H), 1.75 (dd, J = 9.7, 16.8 Hz, 1H), 1.52 (s, 3H), 1.01 - 0.82 (m,4H). [M+H] = 409.10.

Example 415.5-[3,5-Dimethyl-4-(morpholin-4-ylmethyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 2H), 4.34 (s, 3H), 2.74 (s, 4H), 2.38(s, 4H), 2.35 (s, 4H), 1.50 (s, 4H), 0.81 (s, 6H). [M+H] = 425.13.

Example 416.6-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.55 (d, J = 2.3 Hz, 1H), 6.62(d, J = 2.3 Hz, 1H), 3.86 (s, 3H), 2.76 (s, 3H), 1.53 (s, 3H), 1.01 -0.87 (m, 4H). [M+H] = 326.99.

Example 417.N-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 7.62 (s, 1H), 3.82 (s, 3H), 2.82(s, 3H), 2.29 (s, 3H), 1.52 (s, 3H), 1.02 - 0.92 (m, 4H). [M+H] =341.00.

Example 418.6-Methyl-4-[(l-methylcyclopropyl)amino]-N-(trimethyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 3.78 (s, 3H), 2.85 (s, 3H), 2.24(s, 3H), 2.17 (s, 3H), 1.52 (s, 3H), 1.01 - 0.92 (m, 4H). [M+H] =355.07.

Example 419.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 9.01 (s, 1H), 8.46 (d, J = 4.3 Hz, 1H), 8.40(s, 1H), 8.03 -7.92 (m, 3H), 7.32 (ddd, J = 1.5, 5.1, 6.8 Hz, 1H), 2.79(s, 3H), 1.54 (s, 3H), 1.01 - 0.86 (m, 4H). [M+H] = 390.28.

Example 420.N-[1-(2-Methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 4.22 (t, J = 5.2 Hz, 2H), 3.72(t, J = 5.2 Hz, 2H), 3.31 (s, 3H), 2.83 (s, 3H), 2.25 (s, 3H), 2.18 (s,3H), 1.51 (s, 3H), 0.99 - 0.86 (m, 4H). [M+H] = 399.02.

Example 421.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 4.64(t, J = 5.9 Hz, 2H), 3.93 (br s, 4H), 3.73 (t, J = 6.0 Hz, 2H), 3.60 -3.33 (m, 4H), 2.72 (s, 3H), 1.51 (s, 3H), 0.91 - 0.81 (m, 4H). [M+H] =426.23.

Example 422.5-[4-(6-Methoxypyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.68 - 7.60 (m, 1H), 6.88 (d, J= 7.2 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.79 - 3.97 (m, 1H), 3.92 (s,3H), 3.33 (td, J = 1.6, 3.2 Hz, 13H), 3.09 - 2.95 (m, 1H), 2.58 (s, 3H),2.03 (br s, 2H), 1.87 (br s, 2H), 1.54 (s, 3H), 1.06 - 0.82 (m, 4H).[M+H] = 422.2.

Example 423.5-[4-(5-Methoxy-4-methylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.29 (s, 1H), 4.01 - 3.92 (m,3H), 3.16 (tt, J = 3.7, 11.5 Hz, 1H), 2.57 (s, 3H), 2.46 (s, 3H), 2.15 -1.79 (m, 4H), 1.55 (s, 3H), 1.02 - 0.83 (m, 4H). [M+H] = 436.95.

Example 424.2-(4-Fluorophenyl)-7-(6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.06 (br s, 2H), 7.27 (t, J =8.7 Hz, 2H), 4.70 (br s, 2H), 4.17 - 3.71 (m, 2H), 2.73 (br s, 2H), 2.60(s, 3H), 1.49 (s, 3H), 0.95 - 0.82 (m, 4H). [M+H] = 474.97.

Example 425.2-(Methoxymethyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 4.61 (br s, 2H), 4.35 (s, 2H),3.90 (br s, 2H), 3.45 (s, 3H), 2.67 (br s, 2H), 2.57 (s, 3H), 1.48 (s,3H), 0.94 - 0.82 (m, 4H). [M+H] = 425.30.

Example 426.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.93 - 7.82 (m, 2H), 7.19 (d, J= 7.6 Hz, 1H), 2.84 (s, 3H), 2.57 (s, 3H), 1.54 (s, 3H), 1.03 - 0.92 (m,4H). [M+H] = 338.31.

Example 427.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H), 7.66(s, 1H), 7.36 (d, J = 5.7 Hz, 1H), 2.82 (s, 3H), 2.57 (s, 3H), 1.53 (s,3H), 1.02 - 0.89 (m, 4H). [M+H] = 338.34.

Example 428.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H), 8.01(d, J = 7.3 Hz, 1H), 7.36 - 7.30 (m, 1H), 2.91 (s, 3H), 2.45 (s, 3H),1.54 (s, 3H), 1.05 - 0.93 (m, 4H). [M+H] = 338.32.

Example 429.N-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H),4.35 - 4.29 (m, 2H), 3.75 (t, J = 5.1 Hz, 2H), 3.34 (s, 3H), 2.80 (s,3H), 1.55 (s, 3H), 1.12 - 1.01 (m, 4H). [M+H] = 371.36.

Example 430.N-{Bicyclo[1.1.1]pentan-1-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 2.67 (s, 3H), 2.53 (s, 1H), 2.23(s, 6H), 1.54 (s, 3H), 1.02 - 0.86 (m, 4H). [M+H] = 313.2.

Example 431.6-Methyl-N-(1-methylcyclopropyl)-5-{4-[5-(trifluoromethyl)pyrimidin-2-yl]piperidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 2H), 8.40 (s, 1H), 4.72 - 3.86 (m,2H), 3.56 -3.34 (m, 3H), 2.57 (s, 3H), 2.18 (br s, 2H), 2.09 - 1.82 (m,2H), 1.54 (s, 3H), 1.00 - 0.86 (m, 4H). [M+H] = 461.39.

Example 432.N-(1,4-Dimethyl-1H-pyrazol-3-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.43 (s, 1H), 3.84 (s, 3H), 2.79(s, 3H), 2.01 (s, 3H), 1.51 (s, 3H), 0.98 - 0.85 (m, 4H). [M+H] =341.34.

Example 433.N-(Dimethyl-1,3-thiazol-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 2.94 (s, 3H), 2.26 (s, 3H), 2.24(s, 3H), 1.57 (s, 3H), 1.05 - 1.00 (m, 2H), 0.99 - 0.95 (m, 2H). [M+H] =358.31.

Example 434.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyridazin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J = 8.7 Hz, 1H), 8.42 (s, 1H), 7.94 -7.88 (m, 1H), 2.82 (s, 3H), 2.73 (s, 3H), 1.53 (s, 3H), 1.01 - 0.88 (m,4H). [M+H] = 339.33.

Example 435.6-Methyl-N-(1-methyl-1H-imidazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.35 (s, 1H), 7.60 (d, J = 1.6Hz, 1H), 3.92 (s, 3H), 2.77 (s, 3H), 1.50 (s, 3H), 0.92 - 0.79 (m, 4H).[M+H] = 327.33.

Example 436.N-(5-Fluoro-6-methylpyridin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.04 (dd, J = 3.3, 8.9 Hz, 1H),7.57 (t, J = 8.9 Hz, 1H), 2.79 (s, 3H), 2.47 (d, J = 2.8 Hz, 3H), 1.52(s, 3H), 0.99 - 0.86 (m, 4H). [M+H] = 356.33.

Example 437.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyrazin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 2.79(s, 3H), 2.54 (s, 3H), 1.53 (s, 3H), 1.04 - 0.87 (m, 4H). [M+H] =339.34.

Example 438.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(5-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.94 - 7.87 (m,2H), 2.81 (s, 3H), 2.40 (s, 3H), 1.53 (s, 3H), 1.01 - 0.88 (m, 4H).[M+H] = 338.32.

Example 439.N-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 6.43 (s, 1H), 3.74 (s, 3H), 2.75(s, 3H), 2.32 (s, 3H), 1.52 (s, 3H), 0.98 - 0.85 (m, 4H). [M+H] =341.20.

Example 440.N-[1-(2-Methoxyethyl)-1H-pyrazol-3-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.65(d, J = 2.2 Hz, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H),3.35 (s, 3H), 2.80 (s, 3H), 1.55 (s, 3H), 1.07 - 0.93 (m, 4H). [M+H] =371.37.

Example 441.N-(5,6-Dimethylpyrazin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.41 (s, 1H), 2.79 (s, 3H), 2.54(d, J = 5.5 Hz, 6H), 1.53 (s, 3H), 1.00 - 0.88 (m, 4H). [M+H] = 353.35.

Example 442.N-(Dimethyl-1,3-oxazol-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 2.88 (s, 3H), 2.25 (s, 3H), 2.14(s, 3H), 1.55 (s, 3H), 1.12 - 0.95 (m, 4H). [M+H] = 342.32.

Example 443.6-Methyl-N-(4-methyl-1,3-thiazol-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 6.61 (d, J = 1.0 Hz, 1H), 2.95(s, 3H), 2.33 (s, 3H), 1.57 (s, 3H), 1.07 - 0.95 (m, 4H). [M+H] =344.29.

Example 444.4-(6-Fluoropyridin-2-yl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidine-4-carbonitrile.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.06 (q, J = 8.0 Hz, 1H), 7.64(dd, J = 2.2, 7.5 Hz, 1H), 7.10 (dd, J = 2.7, 8.2 Hz, 1H), 4.35 (br s,2H), 3.50 (br s, 2H), 2.59 (s, 3H), 2.28 (br s, 4H), 1.54 (s, 3H),1.02 - 0.79 (m, 4H). [M+H] = 435.4.

Example 445.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)-1H-pyrazol-3-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.62(d, J = 2.2 Hz, 1H), 4.47 (spt, J = 6.6 Hz, 1H), 2.77 (s, 3H), 1.52 (s,3H), 1.50 (d, J = 6.7 Hz, 6H), 1.00 -0.84 (m, 4H). [M+H] = 355.38.

Example 446.N-[1-(3-Fluoropyridin-2-yl)-1H-pyrazol-3-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 8.35(d, J = 5.0 Hz, 1H), 7.85 (dd, J = 8.3, 11.1 Hz, 1H), 7.44 (td, J = 4.0,8.2 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 2.80 (s, 3H), 1.54 (s, 3H),1.00 - 0.87 (m, 4H). [M+H] = 408.36.

Example 447.N-[1-(3-Fluoropyridin-2-yl)-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1H), 8.39 (s, 1H), 8.37 (d, J = 4.6Hz, 1H), 8.05 (s, 1H), 7.92 - 7.84 (m, 1H), 7.47 (td, J = 4.1, 8.2 Hz,1H), 2.79 (s, 3H), 1.54 (s, 3H), 1.00 - 0.87 (m, 4H). [M+H] = 408.36.

Example 448.6-Methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 6.79 (d, J = 1.2 Hz, 1H), 4.69(s, 2H), 2.75 (s, 3H), 2.35 (d, J = 1.1 Hz, 3H), 1.53 (s, 3H), 1.00 -0.81 (m, 4H). [M+H] = 342.3.

Example 449.N-[(2-Methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 5.0 Hz, 1H), 8.45 (s, 1H), 7.15(d, J = 5.1 Hz, 1H), 4.70 (s, 2H), 4.03 (s, 3H), 2.86 (s, 3H), 1.53 (s,3H), 1.03 - 0.89 (m, 4H). [M+H] = 369.4.

Example 450.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.38 (s, 1H), 8.15 (dd, J = 2.1,8.3 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 4.84 (s, 2H), 2.81 (s, 3H), 1.52(s, 3H), 0.96 - 0.82 (m, 4H). [M+H] = 406.4.

Example 451.6-Methyl-N-(4-methyl-1,3-oxazol-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 7.32 (d, J = 1.5 Hz, 1H), 2.87(s, 3H), 2.21 (d, J = 1.2 Hz, 3H), 1.54 (s, 3H), 1.07 - 1.02 (m, 2H),0.96 - 0.92 (m, 2H). [M+H] = 328.20.

Example 452. 6-Methyl-N-(3-methyl-1 24-oxadiazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 2.85 (s, 3H), 2.40 (s, 3H), 1.53(s, 3H), 1.09 - 0.90 (m, 4H). [M+H] = 329.30.

Example 453.6-Methyl-N-(2-methyl-1,3-thiazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.64 (s, 1H), 2.80 (s, 3H), 2.70(s, 3H), 1.55 (s, 3H), 1.03 - 0.96 (m, 2H), 0.96 - 0.90 (m, 2H). [M+H] =344.22.

Example 454.6-Methyl-N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 2.90 (s, 3H), 2.53 (s, 3H), 1.56(s, 3H), 0.97 (d, J = 19.4 Hz, 4H). [M+H] = 345.18.

Example 455.6-Methyl-5-{4-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.41 (s, 1H), 5.03 - 4.87 (m,2H), 4.02 (br s, 2H), 3.01 - 2.92 (m, 2H), 2.59 (s, 3H), 2.54 - 2.49 (m,3H), 1.48 (s, 3H), 0.96 - 0.83 (m, 4H). [M+H] = 379.40.

Example 456.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(oxan-4-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.16 (s, 1H), 7.69 (s, 1H),4.51 - 4.38 (m, 1H), 4.08 (dd, J = 2.6, 10.7 Hz, 2H), 3.59 (dt, J = 2.9,11.5 Hz, 2H), 2.75 (s, 3H), 2.16 - 2.01 (m, 4H), 1.53 (s, 3H), 1.01 -0.88 (m, 4H). [M+H] = 397.38.

Example 457.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 4.88 (s, 2H), 2.76 (s, 3H), 1.52(s, 3H), 1.05 - 0.66 (m, 4H). [M+H] = 397.3.

Example 458.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyrimidin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.64 (d, J = 5.1 Hz, 1H), 8.46 (s, 1H), 7.33(d, J = 5.3 Hz, 1H), 4.82 (s, 2H), 2.90 (s, 3H), 2.57 (s, 3H), 1.54 (s,3H), 1.05 - 0.91 (m, 4H). [M+H] = 353.4.

Example 459.N-[(4,6-Dimethylpyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.23 (s, 1H), 4.78 (s, 2H), 2.92(s, 3H), 2.52 (s, 6H), 1.53 (s, 3H), 1.04 - 0.86 (m, 4H). [M+H] = 367.4.

Example 460.6-Methyl-4-[(l-methylcyclopropyl)amino]-N-[(5-methylpyrazin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 4.76(s, 2H), 2.77 (s, 3H), 2.58 (s, 3H), 1.52 (s, 3H), 1.00 - 0.79 (m, 4H).[M+H] = 353.4.

Example 461.6-Methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.45 (s, 1H), 4.73 (s, 2H), 2.80 (s, 3H), 2.62(s, 3H), 1.54 (s, 3H), 1.09 - 0.90 (m, 4H). [M+H] = 343.3.

Example 462. Methyl2-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}azetidin-3-yl)pyrimidine-5-carboxylate.

¹H NMR (400 MHz, CD₃OD) δ 9.29 (s, 2H), 8.39 (s, 1H), 4.74 - 4.66 (m,2H), 4.57 (br s, 2H), 4.32 (tt, J = 5.8, 8.9 Hz, 1H), 4.00 (s, 3H), 2.65(s, 3H), 1.55 (s, 3H), 1.02 - 0.84 (m, 4H). [M+H] = 423.4.

Example 463.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 9.34 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 9.7Hz, 1H), 7.71 (dd, J = 1.2, 9.7 Hz, 1H), 5.21 (s, 2H), 2.75 (s, 3H),1.50 (s, 3H), 0.89 (s, 4H). [M+H] = 446.3.

Example 464.N-[(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.68 (s, 2H), 2.76 (s, 3H), 2.30(tt, J = 4.8, 8.3 Hz, 1H), 1.53 (s, 3H), 1.35 - 1.24 (m, 2H), 1.22 -1.13 (m, 2H), 1.01 - 0.83 (m, 4H). [M+H] = 369.4.

Example 465.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yloxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.39 (s, 1H), 5.48 (td, J = 6.2,12.4 Hz, 1H), 4.78 (br s, 2H), 4.18 - 3.60 (m, 2H), 2.79 (br s, 2H),2.57 (s, 3H), 1.47 (s, 3H), 1.38 (d, J = 6.1 Hz, 6H), 0.84 (br s, 4H).[M+H] = 423.44.

Example 466.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyridin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.44(s, 1H), 8.38 (br s, 1H), 7.56 (s, 1H), 7.37 (d, J = 5.3 Hz, 1H), 4.81(d, J = 5.3 Hz, 2H), 2.76 (s, 3H), 2.57 (s, 3H), 1.52 (s, 3H), 0.90 -0.72 (m, 4H). [M+H] = 352.4.

Example 467.6-Methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CDCl₃) δ 8.73 (br s, 1H), 8.47 (s, 1H), 7.39 (s, 1H),7.05 (br s, 1H), 4.89 (d, J = 5.1 Hz, 2H), 2.75 (s, 3H), 2.49 (s, 3H),1.55 (s, 3H), 0.93 - 0.75 (m, 4H). [M+H] = 358.3.

Example 468.6-Methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 4.98 (s, 2H), 2.78 (s, 3H), 2.76(s, 3H), 1.54 (s, 3H), 1.04 - 0.86 (m, 4H). [M+H] = 359.3.

Example 469.N,6-Dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.99 - 7.11 (m, 2H), 3.84 (s,3H), 3.47 (s, 3H), 2.54 - 1.88 (m, 3H), 1.54 (s, 3H), 1.04 - 0.91 (m,4H). [M+H] = 341.36.

Example 470.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.64 (s, 1H), 7.26 (s, 1H),5.09 - 4.93 (m, 1H), 3.81 (s, 3H), 2.20 (s, 3H), 1.54 (s, 3H), 1.20 (d,J = 6.7 Hz, 6H), 1.01 - 0.89 (m, 4H). [M+H] = 369.3.

Example 471.6-Methyl-N-(1-methylcyclopropyl)-5-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine.

¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 4.92(br s, 2H), 4.01 (br s, 2H), 3.06 - 2.99 (m, 2H), 2.62 (s, 3H), 1.49 (s,3H), 1.01 - 0.92 (m, 4H). [M+H] = 365.38.

Example 472.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide.

¹H NMR (400 MHz, CD₃OD) δ 8.67 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.33(s, 1H), 8.12 (dt, J = 1.6, 7.8 Hz, 1H), 7.78 (s, 1H), 7.66 - 7.58 (m,1H), 7.41 (d, J = 7.9 Hz, 1H), 5.60 (s, 2H), 2.78 (s, 3H), 1.54 (s, 3H),1.03 - 0.91 (m, 4H). [M+H] = 404.40.

Example 473.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.84 (d, J = 4.8 Hz, 2H), 8.42(s, 1H), 8.07 (s, 1H), 7.43 (t, J = 4.8 Hz, 1H), 2.80 (s, 3H), 1.55 (s,3H), 1.03 - 0.89 (m, 4H). [M+H] = 391.37.

Example 474.5-{4-[(4-Fluorophenyl)methyl]piperazine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furor2,3-d1pyrimidin-4-amine

[M+H] = 424.2.

Example 475.N-[1-(4-Methoxyphenyl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 395.2.

Example 476.N-[1-(3-Methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 395.2.

Example 477.N-[(4-Fluorophenyl)methyl]-N-(3-methoxypropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 427.2.

Example 478.N-[(1S)-1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 479.N-[(1R)-1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 480.N-[(1S)-1-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 481.5-[4-(4-Methoxypyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-dlpyrimidin-4-amine

[M+H] = 424.2.

Example 482.N-[(1S)-1-(2-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 483.N-[(3-Fluoro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 484.N-[(1R)-1-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 485.N-[(1S)-1-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 486.N-[1-(2,5-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 387.2.

Example 487.N-[(4-Hydroxy-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 488.N-[(3-Chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 401.2.

Example 489.N-ethyl-N-[(4-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 395.2.

Example 490.N-[1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 491.N-[2-Hydroxy-3-(4-methoxyphenoxy)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 427.2.

Example 492.N-{[3-(4-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 422.2.

Example 493.N-[(7-Methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 494.N-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 422.2.

Example 495.N-[(3,5-Dimethoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 397.2.

Example 496.5-{3-[(2-Fluorophenyl)methoxy]azetidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 411.2.

Example 497.5-{3-[(3-Fluorophenyl)methoxy]azetidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 411.2.

Example 498.N-[(4-Methoxy-3,5-dimethylpyridin-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 410.2.

Example 499.6-Methyl-N-(1-methylcyclopropyl)-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl]furo[2,3-d]pyrimidin-4-amine

[M+H] = 343.1.

Example 500.N-[(2-Fluoro-6-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 501.N-[(2-Chloro-3-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 389.1.

Example 502.N-[1-(4-Methoxy-3-methylphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 395.2.

Example 503.N-[(2,6-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 373.2.

Example 504.N-[(2,4-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 373.2.

Example 505.N-[(3,4-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 373.2.

Example 506.5-[2-(3-Fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 395.2.

Example 507.N-[(2-Chloro-4-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 389.1.

Example 508.N-[(4-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-en-1-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 407.2.

Example 509.N-[(4-Ethoxy-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 510.N-[1-(3-Fluoro-4-methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 413.3.

Example 511.7-Methoxy-1-methyl-2-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-ol

[M+H] = 423.3.

Example 512.5-[3-(4-Fluorophenoxy)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 397.2.

Example 513.N-[1-(4-Fluorophenyl)-2-hydroxyethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 514.N-[2-(5-Fluoro-2-methyl-1H-indol-3-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 422.3.

Example 515.N-[(1R)-1-(2,4-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 387.2.

Example 516.N-[(6-Chloro-2-fluoro-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 419.2.

Example 517.5-[4-(3-Methoxyphenyl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 421.3.

Example 518.N-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.2.

Example 519. 5-[4-(46-Dimethoxypyrimidin-2-yl)piperidine-l-carbonyl1-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 453.3.

Example 520.6-Methyl-N-(2-methylbut-3-yn-2-yl)-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 313.2.

Example 521.5-r4-(4-Fluoro-2-methanesulfonylphenyl)piperazine-l-carbonyl1-6-methyl-N-(1-methylcyc1opropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 488.2.

Example 522.5-[4-(2-Fluoro-4-methanesulfonylphenyl)-2-methylpiperazine-1-carbony1]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 502.2.

Example 523.5-[4-(2-Fluoro-4-nitrophenyl)piperazine-1-carbony1]-6-methy1-N-(1-methylcyclopropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 455.2.

Example 524.N-[(4-Methoxy-2-methylphenyl)methy1]-6-methyl-4-r(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.3.

Example 525.N-[(4-Fluoro-2-methoxyphenyl)methy1]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 526.N-[(3-Chloro-5-fluorophenyl)methy1]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 389.2.

Example 527.5-(7-Fluoro-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 381.2.

Example 528.N-[(2-Methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 529.5-[3-(3-Fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 396.2.

Example 530.5-[4-(6-Fluoro-5-methoxypyridin-2-yl)piperidine-1-carbony1]-6-methyl-N-(1-methylcyc1opropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 440.3.

Example 531.5-Fluoro-2-(1-{6-methyl-4-[(1-methylcyc1opropyl)amino]lfuro[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)-N-(propan-2-yl)pyrimidin-4-amine

[M+H] = 468.3.

Example 532.5-[3-(6-Fluoropyridin-2-yl)pyrrolidine-1-carbony1]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 396.3.

Example 533.N-[(5-Cyano-2-fluorophenyl)methy1]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 380.2.

Example 534.N-[(4-Chloro-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 389.1.

Example 535.5-[4-(2,4-Difluorophenyl)piperazine-1-carbony]1-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 428.2.

Example 536.5-[3-(4-Fluorophenyl)piperazine-1-carbony1]-6-methyl-N-(1-methylcyclopropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 410.2.

Example 537.N-[1-(4-Fluorophenyl)propan-2-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 538.N-[2-(3-Ethoxy-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 539.N-[2-(3,5-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 387.2.

Example 540.N-[2-(5-Chloro-2-fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 403.2.

Example 541.5-{4-[(3-Fluorophenyl)methyl1piperazine-l-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 424.2.

Example 542.N-[2-(2,5-Dimethoxyphenyl)ethyll-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 543.N-[2-(2,3-Dimethoxyphenyl)ethyll-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 544.N-[2-(3-Chloro-4-fluorophenyl)ethyll-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 403.2.

Example 545.N-[2-(3,4-Dimethoxyphenyl)ethyll-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 546.N-[1-(3,5-Difluorophenyl)ethyl)]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 387.2.

Example 547.N-[(2-Fluoro-6-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 548.N-[1-(4-Fluorophenyl)propyll-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 549.N-[(5-Chloro-2,4-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)aminofuro[2,3-d]pyrimidine-5-carboxamide

[M+H] = 407.1.

Example 550.N-[(2-Fluoro-3-methlphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 551.N-[(2-Chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 401.2.

Example 552.N-[(2-Ethoxy-6-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 399.2.

Example 553.N-[(4-Fluoro-3-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 554.Af-r(5-Fluoro-2-methylphenyl)methyl1-6-methyl-4-r(l-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 555.N-[1-(3,5-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 556.N-[(1R)-l-(3,4-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 557.N-[2-(2-Methoxyphenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 397.2.

Example 558.N-[2-(2-Methoxyphenoxy)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 411.2.

Example 559.N-[2-(2-Fluorophenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 560.N-[(1R)-1-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 561.N-[(5-Chloro-2-fluorophenyl)methyll-6-methyl-4-[(l-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 389.1.

Example 562.N-[(3-Fluoro-4-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 563. 6-Methyl-4-[(1-methylcyclopropyl)amino-N-[(3 45-trifluorophenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 391.2.

Example 564.N-[(3-Chloro-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 389.1.

Example 565.5-[2-(4-Fluorophenyl)piperidine-1-carbony1]-6-methyl-N-(1-methylcyclopropyl)furoF2,3-d]pyrimidin-4-amine

[M+H] = 409.2.

Example 566.5-[2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furor2,3-d]pyrimidin-4-amine

[M+H] = 407.2.

Example 567.5-r2-(3-Methoxyphenyl)piperidine-l-carbonyl1-6-methyl-/V-(l-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 421.6.

Example 568.N-[3-(5-Fluoro-1H-1,3-benzodiazol-2-yl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 423.2.

Example 569.N-[(5-Fluoro-1H-indol-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 408.2.

Example 570.N-[(5-Methoxy-1H-indol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 406.2.

Example 571.N-[1-(4-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 421.2.

Example 572.N-{[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 421.2.

Example 573.N-(3-Hydroxypropyl)-N-[(4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 574.Af-r(4-Fluorophenyl)methyl1-/V-(3-hydroxypropyl)-6-methyl-4-r(l-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 413.2.

Example 575.N-[(6-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 409.2.

Example 576.5-[4-(2-Fluorophenoxy)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 425.2.

Example 577.5-[4-(4-Fluorophenoxy)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 425.2.

Example 578.N-(2-Hydroxyethyl)-N-[(2-methoxyphenyl)methyll-6-methyl-4-[(l-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 411.3.

Example 579.N-(2-Methoxyethyl)-N-[(2-methoxyphenyl)methyll-6-methyl-4-[(l-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.3.

Example 580.N-(2-Methoxyethyl)-N-[(3-methoxyphenyl)methyl]6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 581.N-[1-(2-Methoxyphenyl)ethyl]N,6-dimethyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 395.3.

Example 582.N-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 421.3.

Example 583.N-[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 423.3.

Example 584.N-[(7-Fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 422.2.

Example 585.N-[2-(4-Fluorophenoxy)ethyll-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 385.2.

Example 586.N-{2-[(4-Methoxyphenyl)sulfanyl]ethyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 413.3.

Example 587.5-[2-(3-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 423.3.

Example 588.N-{[1-(4-Fluorophenyl)pyrrolidin-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 424.3.

Example 589.5-[3-(2-Methoxyphenoxy)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 409.3.

Example 590.5-[3-(3-Methoxyphenoxy)azetidine-l-carbonyll-6-methyl-N-(l-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 409.3.

Example 591.N-Ethyl-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 395.3.

Example 592.N-{3-Methoxy-4-(propan-2-yloxy)phenyl]1methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.3.

Example 593.N-{[1-(3-Fluorophenyl)cyc1opentyl]methyl}-6-methyl-4-(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 423.3.

Example 594.N-{[1-(2-Fluorophenyl)cyclopentyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 423.3.

Example 595.N-[1-(4-Ethoxy-3-fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 413.3.

Example 596.N-{[3-(3-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 422.3.

Example 597.N-[1-(3,4-Dimethoxyphenyl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.3.

Example 598.N-[1-(4-Methoxy-3,5-dimethylphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 409.3.

Example 599.N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 427.3.

Example 600.5-(10-Methoxy-3,4,5,6-tetrahydro-2H-1,5-benzoxazoeine-5-carbonyl)-6-methyl-N-(1-methyleyelopropyl)furo[2,3-d]pyrimidin-4-amine

[M+H] = 423.2.

Example 601.N-Ethyl-N-[(3-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 395.2.

Example 602.N-Ethyl-N-[2-(4-methoxyphenoxy)ethyll-6-methyl-4-[(l-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 603.N-Cyclopropyl-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 407.2.

Example 604.N-[(3-Hydroxy-4-methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino1furor2,3-d1pyrimidine-5-carboxamide

[M+H] = 397.2.

Example 605.N-[3-(4-Methoxyphenoxy)propyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.3.

Example 606.N-[(4-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-1-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 405.3.

Example 607.N-[(4-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-l-yl)furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 393.2.

Example 608.N-[(5-Chloro-2-methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 415.2.

Example 609.N-Ethyl-N-[(4-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 383.3.

Example 610.N-[(2-Chloro-4,5-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 407.2.

Example 611.N-[(2-Fluoro-5-methphenyl)methyl]-6-methyl-4-(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

[M+H] = 369.2.

Example 612.N-[(4-Chloro-2,6-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 407.2.

Example 613.Af-ri-(2-Methoxyphenyl)ethyl1-6-methyl-4-r(l-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 614.N-(2-Fluoro-5-nitrophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 400.2.

Example 615.N-[(1R)-1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 371.2.

Example 616.N-Ethyl-N-[(3-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-di]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 617.N-[2-(3,4-Dimethoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 425.2.

Example 618. N-rI-(4-Fluorophenyl)ethyl1-N,6-dimethyl-4-r(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 383.2.

Example 619.N-[2-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

[M+H] = 381.2.

Example 620.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1-(pyridin-3-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.19 (d, J = 2.0 Hz, 1H), 8.86 (s, 1H), 8.59(d, J = 4.8 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 8.01 (s,1H), 7.82 - 7.73 (m, 1H), 2.79 (s, 3H), 1.54 (s, 3H), 1.03 - 0.88 (m,4H). [M+H] = 390.37.

Example 621.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-4-yl)-1H-pvrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 8.81 (d, J = 7.2 Hz, 2H), 8.44(d, J = 7.3 Hz, 2H), 8.38 (s, 1H), 8.17 (s, 1H), 2.78 (s, 3H), 1.52 (s,3H), 0.97 - 0.84 (m, 4H). [M+H] = 390.37.

Example 622.5-{4-Methoxy-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyc1opropyl)furor2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (br s, 1H), 8.42 (s, 1H), 4.99 (br s,4H), 4.15 - 3.99 (m, 3H), 2.65 (s, 3H), 1.49 (s, 3H), 0.96 - 0.83 (m,4H). [M+H] = 381.38.

Example 623.6-Methyl-N-(1-methylcyclopropyl)-5-[2-(trifluoromethyl)-5H,6H,7H,8H-imidazo[1,2-α]pyrazine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.50 (s, 1H), 7.30 (d, J = 0.98 Hz, 1H), 6.97(s, 1H), 4.95 (br s, 2H), 3.87-4.68 (m, 4H), 2.54 (s, 3H), 1.52 (s, 3H),0.75-0.83 (m, 4H). [M+H] = 421.4.

Example 624.5-{3-Bromo-5H,6H,7H,8H-imidazo[1,2-α]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyc1opropyl)furor2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.50 (s, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 4.88(br s, 2H), 3.89-4.47 (m, 4H), 2.53 (s, 3H), 1.53 (s, 3H), 0.75-0.85 (m,4H). [M+H] = 431.3, 433.3.

Example 625.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(2-methylpyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.66 (d, J = 5.4 Hz, 1H), 8.41 (s, 1H), 7.39(d, J = 5.4 Hz, 1H), 4.73 (s, 2H), 2.86 (s, 3H), 2.72 (s, 3H), 1.52 (s,3H), 1.00 - 0.84 (m, 5H). [M+H] = 353.4.

Example 626.N-{[5-(Chlorodifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 4.87 (br s, 2H), 2.76 (s, 3H),1.52 (s, 3H), 1.03 - 0.74 (m, 4H). [M+H] = 413.3.

Example 627. 6-Methyl-N-[(3-methyl-1 24-oxadiazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 4.85 (br s, 2H), 2.78 (s, 3H),2.39 (s, 3H), 1.52 (s, 3H), 0.97 - 0.84 (m, 4H). [M+H] = 343.4.

Example 628.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.31 (s, 1H), 5.22 - 4.86 (m,2H), 4.40 -3.62 (m, 2H), 3.30 (d, J = 6.8 Hz, 1H), 3.02 (br s, 2H), 2.55(s, 3H), 1.46 (s, 3H), 1.34 - 1.24 (m, 7H), 0.74 (s, 5H). [M+H] = 407.4.

Example 629. 5-{4-Methoxy-5H,6H,7H,8H9H-pyrimido[4,5-d]azepine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.40 (s, 1H), 4.09 (br s, 3H),4.04 - 3.81 (m, 4H), 3.32 - 2.93 (m, 4H), 2.54 (s, 3H), 1.51 (s, 3H),0.89 (s, 4H). [M+H] = 409.40.

Example 630.6-Methyl-N-(1-methylcyc1opropyl)-5-(5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.48 (s, 1H), 8.46 (d, J = 4.16 Hz, 1H), 7.54(d, J = 7.21 Hz, 1H), 7.20 (dd, J = 4.77, 7.70 Hz, 1H), 7.08 (br s, 1H),4.89 (br s, 2H), 4.06 (dd, J = 6.05, 12.17 Hz, 2H), 2.94-3.08 (m, 2H),2.53 (s, 3H), 1.50 (s, 3H), 0.69-0.85 (m, 4H). [M+H] = 364.4.

Example 631.6-Methyl-N-(1-methylcyclopropyl)-5-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.52 (dd, J = 1.59, 4.77 Hz, 1H), 8.49 (s,1H), 7.47 (d, J = 7.09 Hz, 1H), 7.22 (dd, J = 4.83, 7.76 Hz, 1H), 6.95(br s, 1H), 4.85 (br s, 2H), 4.03 (d, J = 15.89 Hz, 2H), 3.17 (t, J =5.87 Hz, 2H), 2.52 (s, 3H), 1.50 (s, 3H), 0.77 (d, J = 12.59 Hz, 4H).[M+H] = 364.4.

Example 632.6-Methyl-5-(2-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.49 (s, 1H), 6.91 (br s, 1H), 5.89 (s, 1H),4.84 (br s, 2H), 4.26 (t, J = 5.07 Hz, 2H), 3.88-4.23 (m, 2H), 2.51 (s,3H), 2.29 (s, 3H), 1.52 (s, 3H), 0.78 (d, J = 15.53 Hz, 4H). [M+H] =367.4.

Example 633.6-Methyl-5-(2-methyl-5H,6H,7H,8H-imidazo[1,2-α]pyrazine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.39 (s, 1H), 6.61 (d, J = 0.86 Hz, 1H), 4.82(br s, 2H), 3.83-4.28 (m, 4H), 2.65 (s, 6H), 2.49 (s, 3H), 2.16 (d, J =0.86 Hz, 3H), 1.47 (s, 3H), 0.70-0.79 (m, 4H). [M+H] = 367.4.

Example 634.5-(6-Methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-6-methyl-N-(1-methyleyelopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.49 (s, 1H), 7.96 (br s, 1H), 6.96 (br s,1H), 6.61 (s, 1H), 4.77 (br s, 2H), 3.94 (s, 3H), 3.92 (d, J = 1.47 Hz,2H), 2.95 (t, J = 5.44 Hz, 2H), 2.50 (s, 3H), 1.51 (s, 3H), 0.71-0.81(m, 4H). [M+H] = 394.4.

Example 635.5-(2-Methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-6-methyl-N-(1-methyleyelopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.49 (s, 1H), 7.31 (br s, 1H), 6.96 (br s,1H), 6.65 (d, J = 8.44 Hz, 1H), 4.73 (br s, 2H), 3.83 - 4.09 (m, 5H),3.02 (br s, 2H), 2.50 (s, 3H), 1.51 (s, 3H), 0.77 (d, J = 16.26 Hz, 4H).[M+H] = 394.4.

Example 636.5-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-4H,5H,6H,7H-pyrazolor[1,5-α]pyrazine-2-carbonitrile

¹H NMR (400 MHz, CDC1₃) δ 8.46-8.54 (m, 1H), 6.88 (s, 1H), 6.54 (s, 1H),4.93 (br s, 2H), 4.39 (t, J = 5.20 Hz, 2H), 3.85-4.30 (m, 2H), 2.54 (s,3H), 1.52 (s, 3H), 0.79 (d, J = 6.11 Hz, 4H). [M+H] = 378.4.

Example 637. 6-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydro-27-naphthyridine-2-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.49 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.42(br s, 1H), 7.15 (d, J = 5.0 Hz, 1H), 6.94 (br s, 1H), 4.86 (br s, 2H),4.22 - 3.68 (m, 2H), 2.99 (t, J = 5.4 Hz, 2H), 2.51 (s, 3H), 1.50 (s,3H), 0.81 - 0.73 (m, 4H). [M+H] = 364.4.

Example 638.6-Methyl-N-(1-methylcyclopropyl)-5-(1-(oxan-4-yl)-3-(trifluoromethyl)-5H,6H,7H,8H-imidazor 1,5-a 1pyrazine-7 -carbonyl1furor2,3-d1pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.44 (s, 1H), 6.94 (s, 1H), 4.88 (br s, 2H),4.28 - 4.19 (m, 2H), 4.04 (dd, J = 3.2, 11.2 Hz, 4H), 3.48 (t, J = 11.7Hz, 2H), 2.76 (t, J = 11.8 Hz, 1H), 2.51 (s, 3H), 1.92 (dq, J = 4.0,12.4 Hz, 2H), 1.68 (d, J = 12.7 Hz, 2H), 1.49 (s, 3H), 0.77 (d, J = 8.7Hz, 4H). [M+H] = 505.5.

Example 639.6-Methyl-5-[3-methyl-1-(oxan-4-yl)-5H,6H,7H,8H-imidazo[1,5-α]pyrazine-7-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.46 (s, 1H), 4.81 (s, 2H), 4.04 (dd, J = 4.0,11.1 Hz, 4H), 3.98 - 3.92 (m, 2H), 3.48 (dt, J = 1.8, 11.9 Hz, 2H), 2.67(t, J = 11.9 Hz, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 1.98 - 1.89 (m, 3H),1.65 (d, J = 11.5 Hz, 2H), 1.50 (s, 3H), 0.85 - 0.73 (m, 4H). [M+H] =451.5.

Example 640.5-{5H,6H,7H,8H-Imidazo[1,5-α]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furor2,3-d1pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.44 (s, 1H), 7.53 (s, 1H), 6.87 (s, 1H), 4.87(br s, 2H), 4.22 - 4.16 (m, 2H), 4.10 (br s, 2H), 2.50 (s, 3H), 2.04 (brs, 1H), 1.49 (s, 3H), 0.83 - 0.71 (m, 4H). [M+H] = 353.4.

Example 641.5-{3-Bromo-4H,5H,6H,7H-pyrazolo[1,5-α]lpyrazine-5-carbonyl}-6-methyl-N-(1-methyleyelopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.55 - 8.49 (m, 1H), 7.54 (s, 1H), 6.94 (br s,1H), 4.78 (s, 2H), 4.37 - 4.30 (m, 2H), 4.17 (br s, 2H), 2.53 (s, 3H),1.53 (s, 3H), 0.87 - 0.76 (m, 4H). [M+H] = 431.3.

Example 642.5-(6-Chloro-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-6-methyl-N-(1-methyleyelopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.49 (s, 1H), 8.20 (s, 1H), 7.21 (s, 1H), 6.93(br s, 1H), 4.84 (br s, 2H), 3.92 (br s, 2H), 2.98 (t, J = 5.6 Hz, 2H),2.51 (s, 3H), 1.51 (s, 3H), 0.77 (d, J = 10.9 Hz, 4H). [M+H] = 398.3.

Example 643.N-Methoxy-N,6-dimethyl-4-[(1-methyleyelopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 3.65 (s, 3H), 3.46 (s, 3H), 2.58(s, 3H), 1.53 (s, 3H), 0.99 - 0.82 (m, 4H). [M+H] = 291.3.

Example 644.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[[2-(propan-2-yl)pyrimidin-4-yl1methyl}furor2,3-d1pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, J = 5.3 Hz, 1H), 8.43 (s, 1H), 7.38(d, J = 5.4 Hz, 1H), 4.76 (s, 2H), 3.22 (td, J = 7.0, 13.8 Hz, 1H), 2.88(s, 3H), 1.52 (s, 3H), 1.36 (d, J = 6.8 Hz, 6H), 1.04 - 0.85 (m, 4H).[M+H] = 381.4.

Example 645.N-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.10 (s, 1H), 7.64 (s, 1H), 3.67(td, J = 3.5, 7.3 Hz, 1H), 2.75 (s, 3H), 1.53 (s, 3H), 1.16 - 1.04 (m,4H), 1.01 - 0.87 (m, 4H). [M+H] = 353.36.

Example 646.6-Methyl-N-[(1-methyl-177-pyrazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 4.45(s, 2H), 3.86 (s, 3H), 2.67 (s, 3H), 1.52 (s, 3H), 1.03 - 0.90 (m, 4H).[M+H] = 341.36.

Example 647.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyrimidin-5-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDC1₃) δ 9.13 (s, 1H), 8.89 (s, 2H), 8.40 (s, 1H), 4.68(s, 2H), 2.75 (s, 3H), 1.53 (s, 3H), 1.00 - 0.85 (m, 5H). [M+H] = 339.3.

Example 648.N-{5H,6H,7H-Cyclopenta[d]1pyrimidin-2-ylmethyl}-6-methyl-4-(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.43 (s, 1H), 4.81 (s, 2H),3.09 - 2.99 (m, 4H), 2.87 (s, 3H), 2.22 (quin, J = 7.7 Hz, 2H), 1.54 (s,3H), 1.03 - 0.88 (m, 4H). [M+H] = 379.4.

Example 649.6-Methyl-N-{[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl1methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.82 (br s, 1H), 8.38 (s, 1H), 7.72 (s, 1H),4.92 - 4.88 (m, 2H), 2.88 (s, 3H), 2.69 (s, 3H), 1.52 (s, 3H), 0.95 -0.82 (m, 4H). [M+H] = 421.4.

Example 650.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (d, J = 2.7 Hz, 1H), 8.34 (s, 1H), 8.18(d, J = 7.3 Hz, 1H), 8.13 (dd, J = 2.6, 9.0 Hz, 1H), 8.09 (d, J = 5.4Hz, 1H), 7.83 (dd, J = 5.4, 9.0 Hz, 1H), 4.27 - 4.17 (m, 1H), 4.03 (d, J= 13.2 Hz, 2H), 3.21 (t, J = 11.7 Hz, 2H), 2.66 (s, 3H), 2.17 (d, J =11.1 Hz, 2H), 1.78 (dq, J = 4.0, 11.9 Hz, 2H), 1.51 (s, 3H), 0.96 - 0.83(m, 4H). [M+H] = 407.40.

Example 651.6-Methyl-N-(2-methyl-1,3-benzoxazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.63 -7.53 (m, 2H), 2.78 (s, 3H), 2.66 (s, 3H), 1.52 (s, 3H), 0.99 - 0.83 (m,4H). [M+H] = 378.37.

Example 652.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyrimidin-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.18 - 9.12 (m, 1H), 8.76 (d, J = 5.3 Hz, 1H),8.50 (s, 1H), 8.28 (s, 1H), 7.56 (d, J = 5.1 Hz, 1H), 4.74 (s, 2H), 2.76(s, 3H), 1.49 (s, 3H), 0.88 - 0.68 (m, 4H). [M+H] = 339.3.

Example 653.6-Methyl-4-(1-methylcyclopropyl)amino]-N-(pyrimidin-2-ylmethyl)furo[12,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.82 (d, J = 5.0 Hz, 2H), 8.51 (s, 1H), 8.28(s, 1H), 7.43 (t, J = 4.9 Hz, 1H), 4.84 (s, 2H), 2.77 (s, 3H), 1.51 (s,3H), 0.86 - 0.67 (m, 4H). [M+H] = 339.2.

Example 654.6-Methyl-4-[(1-methylcyclopropyl)amino]-/V-l(6-methylpyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J = 1.2 Hz, 1H), 8.39 (s, 1H), 7.44(s, 1H), 4.70 (s, 2H), 2.80 (s, 3H), 2.54 (s, 3H), 1.50 (s, 3H), 0.95 -0.85 (m, 4H). [M+H] = 353.20.

Example 655.6-Methyl-4-(1-methylcyclopropyl)amino]-N-[4-(morpholin-4-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.16(d, J = 8.9 Hz, 2H), 3.95 - 3.88 (m, 4H), 3.30 - 3.27 (m, 4H), 2.79 (s,3H), 1.54 (s, 3H), 1.02 - 0.92 (m, 4H). [M+H] = 408.40.

Example 656.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(morpholin-4-yl)pyridazin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 8.27 (d, J = 9.7 Hz, 1H), 7.78(d, J = 10.1 Hz, 1H), 3.90 - 3.83 (m, 4H), 3.71 - 3.64 (m, 4H), 2.78 (s,3H), 1.51 (s, 3H), 0.93 - 0.80 (m, 4H). [M+H] = 410.30.

Example 657.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(morpholin-4-yl)pyrimidin-5-yl]furo[2,3-6]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 2H), 8.41 (s, 1H), 3.82 - 3.74 (m,8H), 2.79 (s, 3H), 1.52 (s, 3H), 0.99 - 0.87 (m, 4H). [M+H] = 410.30.

Example 658.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(morpholin-4-yl)pyrazin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.86 (d, J = 1.3 Hz, 1H), 8.39 (s, 1H), 8.06(d, J = 1.3 Hz, 1H), 3.86 - 3.80 (m, 4H), 3.61 - 3.54 (m, 4H), 2.78 (s,3H), 1.52 (s, 3H), 1.00 - 0.84 (m, 4H). [M+H] = 410.30.

Example 659.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyrimidin-5-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.95 (s, 1H), 8.74 (br s, 1H), 8.67 (s, 1H),8.38 (s, 1H), 4.67 (s, 2H), 2.71 (s, 3H), 2.65 (s, 3H), 1.50 (s, 3H),0.95 - 0.87 (m, 4H). [M+H] = 353.27.

Example 660.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.16(d, J = 7.5 Hz, 1H), 8.12 (dd, J = 1.5, 2.7 Hz, 1H), 7.76 (d, J = 2.7Hz, 1H), 4.44 (d, J = 13.6 Hz, 2H), 4.29 -4.17 (m, 1H), 3.22 - 3.10 (m,2H), 2.66 (s, 3H), 2.16 - 2.06 (m, 2H), 1.66 (dq, J = 4.0, 12.0 Hz, 2H),1.52 (s, 3H), 0.97 - 0.84 (m, 4H). [M+H] = 408.36.

Example 661.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-oxo-1,6-dihydropyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.21 (d, J = 0.7 Hz, 1H), 6.40(d, J = 1.0 Hz, 1H), 4.49 (s, 2H), 2.79 (s, 3H), 1.51 (s, 3H), 0.97 -0.90 (m, 4H). [M+H] = 355.30.

Example 662.6-Methyl-N-[(2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)methyll-4-[(l-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 6.23 (s, 1H), 4.44 (s, 2H), 2.79(s, 3H), 2.42 (s, 3H), 1.50 (s, 3H), 0.96 - 0.87 (m, 4H). [M+H] =369.20.

Example 663.5-14-Methoxy-5H,6H,7H,877-pyrido[4,3-6ripyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.41 (s, 1H), 4.73 (br s, 2H),4.09 (s, 3H), 4.06 - 3.87 (m, 2H), 3.06 - 2.99 (m, 2H), 2.60 (s, 3H),1.48 (s, 3H), 0.94 - 0.85 (m, 4H). [M+H] = 395.30.

Example 664. 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,3-oxazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 6.77 (d, J = 1.0 Hz, 1H), 4.68(s, 2H), 3.08 -2.96 (m, 1H), 2.73 (s, 3H), 1.50 (s, 3H), 1.28 (d, J =6.8 Hz, 6H), 0.95 - 0.84 (m, 4H). [M+H] = 370.32.

Example 665.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (d, J = 4.5 Hz, 3H), 8.18 (d, J = 7.3 Hz,1H), 6.69 (t, J = 4.9 Hz, 1H), 4.73 (d, J = 13.4 Hz, 2H), 4.32 - 4.22(m, 1H), 3.26 - 3.17 (m, 2H), 2.70 (s, 3H), 2.12 (dd, J = 3.0, 12.8 Hz,2H), 1.66 (dq, J = 4.0, 12.0 Hz, 2H), 1.55 (s, 3H), 1.04 - 0.90 (m, 4H).[M+H] = 408.40.

Example 666.N-[(6-Methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.73 (s, 1H), 8.39 (s, 1H), 6.86 (s, 1H), 4.63(s, 2H), 4.01 (s, 3H), 2.78 (s, 3H), 1.50 (s, 3H), 0.90 (d, J = 9.4 Hz,4H). [M+H] = 369.30.

Example 667.N-[(6-Methoxy-2-methylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furor2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 6.76 (s, 1H), 4.63 (s, 2H), 4.03(s, 3H), 2.80 (s, 3H), 2.64 (s, 3H), 1.49 (s, 3H), 0.95 - 0.83 (m, 4H).[M+H] = 383.30.

Example 668.6-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 8.47 (d, J = 5.14 Hz, 1H), 7.08(br s, 1H), 6.93 (br s, 1H), 4.83 (br s, 2H), 3.97 (d, J = 19.20 Hz,2H), 3.01 (t, J = 5.44 Hz, 2H), 2.51 (s, 3H), 1.51 (s, 3H), 0.77 (d, J =13.69 Hz, 4H). [M+H] = 364.3.

Example 669.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)pyrrolidin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 8.03 (ddd, J = 1.7, 7.2, 9.1 Hz,1H), 7.93 (dd, J = 0.9, 6.5 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H), 6.98 (t,J = 6.5 Hz, 1H), 4.93 - 4.86 (m, 1H), 4.05 (dd, J = 6.6, 10.9 Hz, 1H),3.88 - 3.72 (m, 2H), 3.66 (dd, J = 4.9, 11.0 Hz, 1H), 2.66 (s, 3H),2.61 - 2.49 (m, 1H), 2.35 (qd, J = 6.6, 13.3 Hz, 1H), 1.51 (s, 3H),0.93 - 0.81 (m, 4H). [M+H] = 393.30.

Example 670.6-Methyl-4-[(1-methylcyclopropyl)amino1-N-[1-(2-methylpyrimidin-4-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.08(d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 5.13 (d, J = 11.0 Hz,1H), 4.39 - 4.20 (m, 2H), 3.57 - 3.33 (m, 2H), 2.65 (s, 3H), 2.58 (s,3H), 2.22 (br s, 2H), 1.68 (d, J = 13.3 Hz, 2H), 1.51 (s, 3H), 0.91-0.80 (m, 4H). [M+H] = 422.40.

Example 671.6-Methyl-4-[(1-methylcyclopropyl)amino1-N-[1-(6-methylpyrimidin-4-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 7.2Hz, 1H), 7.05 (s, 1H), 5.09 (br s, 1H), 4.40 - 4.14 (m, 2H), 3.60 - 3.33(m, 2H), 2.64 (s, 3H), 2.48 (s, 3H), 2.22 (d, J = 12.2 Hz, 2H), 1.69 (d,J = 10.5 Hz, 2H), 1.50 (s, 3H), 0.91 - 0.79 (m, 4H). [M+H] = 422.40.

Example 672.N-[1-(2,6-Dimethylpyrimidin-4-yl)piperidin-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 8.19 (d, J = 7.2 Hz, 1H), 6.90(s, 1H), 5.11 (d, J = 12.7 Hz, 1H), 4.39 - 4.20 (m, 2H), 3.46 (t, J =12.5 Hz, 1H), 3.28 (br s, 1H), 2.64 (s, 3H), 2.56 (s, 3H), 2.44 (s, 3H),2.29 - 2.12 (m, 2H), 1.68 (t, J = 12.5 Hz, 2H), 1.51 (s, 3H), 0.90 -0.80 (m, 4H). [M+H] = 436.40.

Example 673.6-Methyl-N-[(2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.95 (s, 1H), 4.39 (s, 2H), 2.70(s, 3H), 2.46 (s, 3H), 1.50 (s, 3H), 0.97 - 0.85 (m, 4H). [M+H] =369.30.

Example 674.N-{[2-(1H-Imidazol-1-yl)pyridin-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.76 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.39(s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 5.1 Hz,1H), 4.78 (s, 2H), 2.78 (s, 3H), 1.48 (s, 3H), 0.88 - 0.81 (m, 4H).[M+H] = 404.30.

Example 675.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[2-(morpholin-4-yl)pyridin-4-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 7.96 (d, J = 6.5 Hz, 1H), 7.33(s, 1H), 7.05 (dd, J = 1.2, 6.6 Hz, 1H), 4.69 (s, 2H), 3.91 - 3.83 (m,4H), 3.71 - 3.64 (m, 4H), 2.77 (s, 3H), 1.49 (s, 3H), 0.90 - 0.82 (m,4H). [M+H] = 423.40.

Example 676.N-[(4-Methoxy-2-methylpyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.37 (s, 1H), 4.57 (s, 2H), 4.23(s, 3H), 2.74 (s, 3H), 2.71 (s, 3H), 1.50 (s, 3H), 0.95 - 0.84 (m, 4H).[M+H] = 383.28.

Example 677.N-[(2-Chloropyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.65 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 7.50(d, J = 5.1 Hz, 1H), 4.73 (s, 2H), 2.82 (s, 3H), 1.50 (s, 3H), 0.93 -0.84 (m, 4H). [M+H] = 373.20.

Example 678.N-[(6-Fluoro-5-methoxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 7.57 (dd, J = 8.2, 10.1 Hz, 1H),7.30 (d, J = 8.1 Hz, 1H), 4.66 - 4.55 (m, 2H), 3.93 (s, 4H), 2.81 (s,3H), 1.54 (s, 3H), 1.05 - 0.89 (m, 4H). [M+H] = 386.4.

Example 679.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(2-methylpyrimidin-5-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 2H), 8.26 (s, 1H), 4.60 (s, 2H), 2.70(s, 3H), 2.66 (s, 3H), 1.49 (s, 3H), 0.83 - 0.72 (m, 4H). [M+H] = 353.4.

Example 680.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethyl)pyrimidin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.13 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 7.82(d, J = 5.0 Hz, 1H), 4.96 (s, 2H), 2.86 (s, 3H), 1.51 (s, 3H), 0.93 -0.79 (m, 4H). [M+H] = 407.4.

Example 681.2-Cyclopropyl-6-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-one

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 4.78 (br s, 2H), 4.65 (br s,2H), 2.61 (s, 3H), 1.95 (br s, 1H), 1.49 (s, 3H), 1.24 - 1.07 (m, 4H),0.95 - 0.82 (m, 4H). [M+H] = 407.30.

Example 682.6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-2-(propan-2-yl)-3H,4H,5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-one

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 4.94 - 4.85 (m, 2H), 4.70 (d, J= 15.2 Hz, 2H), 2.92 (br s, 1H), 2.62 (s, 3H), 1.49 (s, 3H), 1.30 (br s,6H), 0.95 - 0.82 (m, 4H). [M+H] = 409.30.

Example 683.6-Methyl-N-(1-methylcyclopropyl)-5-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.56 (d, J = 1.96 Hz, 1H), 6.91(br s, 1H), 6.12 (s, 1H), 4.91 (br s, 2H), 4.35 (t, J = 5.26 Hz, 2H),3.91-4.28 (m, 2H), 2.53 (s, 3H), 1.52 (s, 3H), 0.78 (d, J = 14.43 Hz,4H). [M+H] = 353.3.

Example 684.5-{3-Cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.45 (s, 1H), 7.09 (br s, 1H), 6.81 (s, 1H),4.87 (br s, 2H), 4.22 (br s, 2H), 2.63 (d, J = 8.07 Hz, 2H), 2.48 (s,3H), 1.80-1.91 (m, 1H), 1.51 (s, 3H), 1.05-1.11 (m, 4H), 0.82 (br s,2H), 0.76 (s, 2H). [M+H] = 393.3.

Example 685.N-[(6-Methoxypyrimidin-4-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.80 (br s, 1H), 8.43 (s, 1H), 6.89 (br s,1H), 4.82 - 4.67 (m, 2H), 4.02 (br s, 3H), 3.16 (br s, 3H), 2.58 (s,3H), 1.55 (s, 3H), 0.93 (br s, 4H). [M+H] = 261.20.

Example 686.N-(6-Cyclopropylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 1H), 8.41 (s, 1H), 7.39 (s, 1H), 4.67(s, 2H), 2.81 (s, 3H), 2.10 (quin, J = 6.4 Hz, 1H), 1.51 (s, 3H), 1.17 -1.12 (m, 4H), 0.97 - 0.89 (m, 4H). [M+H] = 379.40.

Example 687.5-{2-Cyclopropyl-4-methoxy-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 4.90 (br s, 2H), 4.76 (br s,2H), 4.08 - 3.93 (m, 3H), 2.62 (s, 3H), 2.15 (br s, 1H), 1.48 (s, 3H),1.21 - 1.03 (m, 4H), 0.93 - 0.81 (m, 4H). [M+H] = 421.41.

Example 688.5-[4-Methoxy-2-(propan-2-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 4.93 (br s, 2H), 4.80 (br s,2H), 4.19 - 3.98 (m, 3H), 3.13 (br s, 1H), 2.63 (s, 3H), 1.50 - 1.46 (m,3H), 1.33 (d, J = 4.5 Hz, 6H), 0.93 - 0.81 (m, 4H). [M+H] = 423.42.

Example 689.N-[(2-Cyclopropylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.59 - 8.52 (m, 1H), 8.41 (s, 1H), 7.28 (d, J= 5.3 Hz, 1H), 4.68 (s, 2H), 2.83 (s, 3H), 2.29 - 2.18 (m, 1H), 1.50 (s,3H), 1.15 - 1.09 (m, 4H), 0.97 - 0.88 (m, 4H). [M+H] = 379.41.

Example 690.5-{2-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.38 (s, 1H), 4.94 - 4.86 (m,2H), 3.97 (br s, 2H), 2.98 (t, J = 5.3 Hz, 2H), 2.58 (s, 3H), 1.47 (s,3H), 0.90 - 0.80 (m, 4H). [M+H] = 399.29.

Example 691.N-[(5-tert-Butyl-1,3-oxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1H), 6.65 (s, 1H), 4.58 (s, 2H), 2.62(s, 3H), 1.40 (s, 3H), 1.22 (s, 9H), 0.87 - 0.69 (m, 4H). [M+H] = 384.4.

Example 692.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-oxazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 7.91 - 7.79 (m, 1H), 7.18 - 7.06(m, 1H), 4.85 - 4.76 (m, 2H), 3.10 - 3.05 (m, 3H), 2.45 - 2.42 (m, 3H),1.45 - 1.39 (m, 3H), 0.84 - 0.76 (m, 4H). [M+H] = 342.3.

Example 693.N-[2-(2-Cyclopropylpyrimidin-5-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 2H), 8.38 (s, 1H), 8.27 (br s, 1H),3.75 - 3.68 (m, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.62 (s, 3H), 2.29 - 2.15(m, 1H), 1.52 (s, 3H), 1.13 - 1.06 (m, 4H), 1.01 - 0.89 (m, 4H). [M+H] =393.42.

Example 694.5-{1-Chloro-3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 6.99 (s, 1H), 4.73 (s, 2H), 4.13(br s, 4H), 2.52 (s, 3H), 1.79 - 1.69 (m, 1H), 1.54 (s, 3H), 1.10 - 1.04(m, 2H), 1.03 - 0.96 (m, 2H), 0.83 (br s, 2H), 0.78 (s, 2H). [M+H] =427.3.

Example 695.5-{3-Cyclopropyl-1-iodo-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-6]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 7.00 (br s, 1H), 4.66 (s, 2H),4.14 (br s, 4H), 2.52 (s, 3H), 1.81 - 1.71 (m, 1H), 1.54 (s, 3H), 1.10 -1.05 (m, 2H), 1.04 - 0.96 (m, 2H), 0.87 -0.81 (m, 2H), 0.79 (s, 2H).[M+H] = 519.3.

Example 696.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)pyrimidin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 2H), 8.39 (s, 1H), 4.94 (s, 2H), 2.85(s, 3H), 1.50 (s, 3H), 0.96 - 0.85 (m, 4H). [M+H] = 407.4.

Example 697.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-methylpyridin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 8.29 (t, J = 7.9 Hz, 1H), 7.72(dd, J = 8.0, 12.5 Hz, 2H), 2.80 (s, 3H), 2.79 (s, 3H), 1.49 (s, 3H),0.96 - 0.86 (m, 1H), 0.82 (s, 4H). [M+H] = 352.3.

Example 698.N-[(2-Methoxypyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 2H), 8.39 (s, 1H), 4.55 (s, 2H), 4.01(s, 3H), 2.71 (s, 3H), 1.51 (s, 3H), 0.94 (d, J = 5.9 Hz, 4H). [M+H] =369.30.

Example 699.5-{2-Methoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 2H), 4.83 - 4.76 (m, 2H), 4.05 - 3.87(m, 5H), 2.92 (br s, 2H), 2.59 (s, 3H), 1.48 (s, 3H), 0.89 (d, J = 7.6Hz, 4H). [M+H] = 395.30.

Example 700.N,6-Dimethyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.19 (br s, 1H), 5.00 (s, 2H),3.21 (s, 3H), 2.58 (s, 3H), 2.45 (s, 3H), 1.53 (s, 3H), 0.95 - 0.79 (m,4H). [M+H] = 372.4.

Example 701.N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 7.84 (br s, 1H), 7.67 (br s,1H), 5.09 (br s, 2H), 3.19 (s, 3H), 2.57 (s, 3H), 1.55 (s, 3H), 1.03 -0.80 (m, 4H). [M+H] = 358.3.

Example 702.N,6-Dimethyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.48 (br s, 1H), 4.99 (br s,2H), 3.17 (s, 3H), 2.56 (s, 3H), 2.52 (s, 3H), 1.55 (s, 3H), 0.97 - 0.84(m, 4H). [M+H] = 372.4.

Example 703.6-Methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.13 (d, J = 1.0 Hz, 1H), 4.88(s, 2H), 2.78 (s, 3H), 2.44 (d, J = 0.9 Hz, 3H), 1.53 (s, 3H), 1.03 -0.81 (m, 4H). [M+H] = 358.3.

Example 704.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.18 (s, 1H), 4.94 (s, 2H), 2.77(s, 3H), 1.52 (s, 3H), 1.08 - 0.74 (m, 4H). [M+H] = 412.3.

Example 705.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrimidin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 2H), 8.46 (s, 1H), 4.83 (s, 2H), 2.87(s, 3H), 2.37 (s, 3H), 1.54 (s, 3H), 1.04 - 0.93 (m, 4H). [M+H] = 353.4.

Example 706.N-{[5-(Difluoromethyl)pyrimidin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.29 - 6.78 (m,1H), 4.93 (s, 2H), 2.86 (s, 3H), 1.52 (s, 3H), 0.98 - 0.85 (m, 4H).[M+H] = 389.4.

Example 707.N-{[4-(Difluoromethyl)pyrimidin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J = 5.0 Hz, 1H), 8.40 (s, 1H), 7.68(d, J = 5.0 Hz, 1H), 6.91 - 6.57 (m, 1H), 4.92 (s, 2H), 2.87 (s, 3H),1.52 (s, 3H), 1.01 - 0.82 (m, 4H). [M+H] = 389.4.

Example 708.N-[(2-Cyclopropylpyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 2H), 8.37 (s, 1H), 4.56 (s, 2H), 2.71(s, 3H), 2.22 (quin, J = 6.4 Hz, 1H), 1.51 (s, 3H), 1.12 - 1.07 (m, 4H),0.91 (d, J = 4.2 Hz, 4H). [M+H] = 379.20.

Example 709.5-{4-Methoxy-2-methyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-6]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H), 4.92 (br s, 2H), 4.82 - 4.68 (m,2H), 4.15 -3.97 (m, 3H), 2.61 (s, 6H), 1.48 (s, 3H), 0.88 - 0.78 (m,4H). [M+H] = 395.30.

Example 710.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-5-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 8.90 (s, 2H), 8.36 (s, 1H), 5.29(q, J = 7.2 Hz, 1H), 2.74 (s, 3H), 1.71 (d, J = 7.1 Hz, 3H), 1.49 (s,3H), 0.94 - 0.71 (m, 4H). [M+H] = 353.3.

Example 711.N-[(6-Methoxypyridazin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.24(d, J = 9.2 Hz, 1H), 4.82 (s, 2H), 4.10 (s, 3H), 2.77 (s, 3H), 1.53 (s,3H), 1.00 - 0.90 (m, 4H). [M+H] = 369.30.

Example 712.5-{4-Methoxy-2-methyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.73 (br s, 2H), 4.17 (s, 3H),4.03 (br s, 2H), 3.07 (t, J = 5.4 Hz, 2H), 2.70 (s, 3H), 2.58 (s, 3H),1.47 (s, 3H), 0.88 - 0.79 (m, 4H). [M+H] = 409.23.

Example 713.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-oxazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.92 (d, J = 0.7 Hz, 1H), 7.17(d, J = 0.6 Hz, 1H), 4.74 (s, 2H), 2.75 (s, 3H), 1.51 (s, 3H), 0.99 -0.87 (m, 4H). [M+H] = 328.20.

Example 714.N-[(5-Methoxy-1,3-benzoxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.19(d, J = 2.4 Hz, 1H), 7.00 (dd, J = 2.6, 8.9 Hz, 1H), 4.87 (s, 2H), 3.85(s, 3H), 2.80 (s, 3H), 1.50 (s, 3H), 0.90 - 0.82 (m, 4H). [M+H] =408.20.

Example 715.6-Methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.52(d, J = 2.0 Hz, 1H), 4.88 (s, 2H), 3.98 (s, 3H), 2.74 (s, 3H), 1.48 (s,3H), 0.83 - 0.79 (m, 4H). [M+H] = 341.30.

Example 716.N-[(5-Chloropyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.82 (s, 2H), 8.39 (s, 1H), 4.84 (s, 2H), 2.83(s, 3H), 1.51 (s, 3H), 0.96 - 0.86 (m, 4H). [M+H] = 373.20.

Example 717.6-Methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 4.83 (s, 2H), 2.78 (s, 3H), 2.57(s, 3H), 1.53 (s, 3H), 1.05 - 0.85 (m, 4H). [M+H] = 343.3.

Example 718.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-methylpyridazin-3-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.28 (s, 1H), 7.72 - 7.67 (m, 1H), 7.66 - 7.62(m, 1H), 4.87 (s, 2H), 2.73 (s, 3H), 2.70 (s, 3H), 1.49 (s, 3H), 0.82 -0.73 (m, 4H). [M+H] = 353.4.

Example 719.N-{Imidazo[1,2-a]pyrazin-6-ylmethyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.26 (d, J = 0.7 Hz, 1H), 8.78 (d, J = 1.2 Hz,1H), 8.40 (s, 1H), 8.26 (d, J = 1.1 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H),4.81 (s, 2H), 2.78 (s, 3H), 1.50 (s, 3H), 0.97 - 0.87 (m, 4H). [M+H] =378.30.

Example 720.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-4-yl)azetidin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.67 (d, J = 1.1 Hz, 1H), 8.33 (s, 1H), 8.16(dd, J = 1.5, 7.3 Hz, 1H), 6.74 (dd, J = 0.9, 7.4 Hz, 1H), 5.02 (tt, J =5.4, 8.0 Hz, 1H), 4.80 - 4.71 (m, 2H), 4.44 (d, J = 5.7 Hz, 2H), 2.73(s, 3H), 1.50 (s, 3H), 0.91 - 0.82 (m, 4H). [M+H] = 380.30.

Example 721.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[4-(oxan-4-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.31(d, J = 8.6 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.62 - 3.52 (m, 2H), 2.87 -2.80 (m, 1H), 2.77 (s, 3H), 1.85 - 1.73 (m, 4H), 1.52 (s, 3H), 1.03 -0.88 (m, 4H). [M+H] = 407.36.

Example 722.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethoxy)phenyl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.27(d, J = 8.1 Hz, 2H), 4.62 (s, 2H), 2.68 (s, 3H), 1.50 (s, 3H), 0.94 -0.83 (m, 4H). [M+H] = 421.30.

Example 723.N-{[2-Fluoro-4-(trifluoromethoxy)phenyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.60 - 7.52 (m, 1H), 7.15 (t, J= 7.3 Hz, 2H), 4.65 (s, 2H), 2.68 (s, 3H), 1.50 (s, 3H), 0.94 - 0.84 (m,4H). [M+H] = 439.30.

Example 724.N-[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.30 (s, 1H), 7.77 (dd, J = 4.3, 9.0 Hz, 1H),7.54 (dd, J = 2.3, 8.2 Hz, 1H), 7.38 (dt, J = 2.3, 9.2 Hz, 1H), 3.94 (t,J = 6.4 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 2.62 (s, 3H), 1.40 (s, 3H),0.80 - 0.63 (m, 4H). [M+H] = 409.30.

Example 725.N-[(6-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 - 8.35 (m, 1H), 7.80 (dd, J = 4.3, 9.0Hz, 1H), 7.73 (dd, J = 2.0, 8.4 Hz, 1H), 7.40 (dt, J = 2.2, 9.2 Hz, 1H),5.14 - 5.09 (m, 2H), 4.10 (s, 3H), 2.80 (s, 3H), 1.46 (s, 3H), 0.84 -0.78 (m, 4H). [M+H] = 409.29.

Example 726.N-[(2-Ethylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.67 (d, J = 5.3 Hz, 1H), 8.42 (s, 1H), 7.39(d, J = 5.4 Hz, 1H), 4.74 (s, 2H), 3.02 - 2.94 (m, 2H), 2.85 (s, 3H),1.51 (s, 3H), 1.40 - 1.32 (m, 3H), 0.97 -0.89 (m, 4H). [M+H] = 367.27.

Example 727.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(oxan-4-yl)pyridin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 8.6Hz, 1H), 7.92 (dd, J = 2.1, 8.6 Hz, 1H), 4.14 - 4.05 (m, 2H), 3.67 -3.57 (m, 2H), 3.01 - 2.89 (m, 1H), 2.84 -2.80 (m, 3H), 1.89 - 1.80 (m,4H), 1.55 - 1.53 (m, 3H), 0.98 - 0.87 (m, 4H). [M+H] = 408.29.

Example 728.N-[(Dimethyl-1,3-oxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 4.63 (s, 2H), 2.75 (s, 3H), 2.25(s, 3H), 2.07 (d, J = 0.6 Hz, 3H), 1.51 (s, 3H), 0.97 - 0.87 (m, 4H).[M+H] = 356.20.

Example 729.N-[(5-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.78 (dd, J = 4.3, 9.0 Hz, 1H),7.54 (dd, J = 2.3, 8.2 Hz, 1H), 7.37 (dt, J = 2.4, 9.3 Hz, 1H), 5.05 (s,2H), 2.81 (s, 3H), 1.46 (s, 3H), 0.80 (s, 4H). [M+H] = 395.30.

Example 730.N-[2-(5-Fluoro-1,3-benzoxazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.45 - 8.38 (m, 1H), 8.34 (s, 1H), 7.59 (dd, J= 4.3, 8.9 Hz, 1H), 7.38 (dd, J = 2.6, 8.4 Hz, 1H), 7.16 (dt, J = 2.6,9.2 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.29 (br s, 2H), 2.63 (s, 3H), 1.48(s, 3H), 0.85 (s, 4H). [M+H] = 410.30.

Example 731.N-[(5-Methoxypyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 4.67(s, 2H), 3.97 (s, 3H), 2.72 (s, 3H), 1.51 (s, 3H), 0.96 - 0.86 (m, 4H).[M+H] = 369.20.

Example 732.N-[(5-Cyclopropylpyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J = 1.5 Hz, 1H), 8.49 (s, 1H), 8.37(s, 1H), 4.71 (s, 2H), 2.74 (s, 3H), 2.23 - 2.12 (m, 1H), 1.51 (s, 3H),1.13 - 1.01 (m, 4H), 0.95 - 0.84 (m, 4H). [M+H] = 379.30.

Example 733.N-[(5-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.35 (s, 1H), 7.90 (dd, J = 4.3, 9.2 Hz, 1H),7.55 (dd, J = 2.4, 8.3 Hz, 1H), 7.43 (dt, J = 2.4, 9.3 Hz, 1H), 5.10 (s,2H), 4.13 (s, 3H), 2.80 (s, 3H), 1.46 (s, 3H), 0.80 (s, 4H). [M+H] =409.26.

Example 734.N-[2-(5-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.30 (s, 1H), 7.90 (dd, J = 4.2, 9.2 Hz, 1H),7.55 (dd, J = 2.3, 8.2 Hz, 1H), 7.44 (dt, J = 2.3, 9.2 Hz, 1H), 4.09 (s,3H), 3.93 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 6.5 Hz, 2H), 2.66 (s, 3H),1.40 (s, 3H), 0.80 - 0.60 (m, 4H). [M+H] = 423.30.

Example 735.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(oxan-4-yl)pyridin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 9.16 (d, J = 2.3 Hz, 1H), 8.51 (dd, J = 2.3,8.8 Hz, 1H), 8.40 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 4.11 (d, J = 11.4Hz, 2H), 3.68 - 3.54 (m, 2H), 3.29 - 3.20 (m, 1H), 2.79 (s, 3H), 2.01 -1.89 (m, 4H), 1.51 (s, 3H), 0.95 - 0.83 (m, 4H). [M+H] = 408.30.

Example 736.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(oxan-4-yl)pyrazin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) b 9.33 (s, 1H), 8.43 (s, 1H), 8.40 - 8.36 (m,1H), 4.08 (dd, J = 3.4, 11.2 Hz, 2H), 3.64 - 3.57 (m, 2H), 3.14 - 3.06(m, 1H), 2.80 (s, 3H), 2.01 - 1.90 (m, 2H), 1.90 - 1.82 (m, 2H), 1.53(s, 3H), 1.02 - 0.97 (m, 2H), 0.94 - 0.90 (m, 2H). [M+H] = 409.3.

Example 737.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(morpholin-4-yl)pyridin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (t, J = 5.8 Hz, 1H), 8.41 (s, 1H), 8.26(s, 1H), 7.56 - 7.46 (m, 1H), 6.69 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 7.2Hz, 1H), 4.40 (d, J = 5.7 Hz, 2H), 3.67 -3.57 (m, 4H), 3.45 - 3.33 (m,4H), 2.60 (s, 3H), 1.36 (s, 3H), 0.68 - 0.58 (m, 4H). [M+H] = 423.0.

Example 738.6-Methyl-N-[(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (t, J = 5.7 Hz, 1H), 8.35 - 8.18 (m,2H), 4.68 (d, J = 5.9 Hz, 2H), 4.28 (s, 3H), 2.57 (s, 3H), 1.36 (s, 3H),0.65 (d, J = 4.5 Hz, 4H). [M+H] = 343.0.

Example 739.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J = 5.8 Hz, 1H), 8.32 (s, 1H), 8.25(s, 1H), 6.58 (s, 1H), 4.30 (d, J = 5.5 Hz, 2H), 3.66 - 3.61 (m, 4H),3.36 - 3.24 (m, 4H), 2.57 (s, 3H), 1.36 (s, 3H), 0.63 (d, J = 6.5 Hz,4H). [M+H] = 429.91.

Example 740.6-Methyl-N-[(2-methyl-2H-1,2,3-triazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (t, J = 5.8 Hz, 1H), 8.32 (s, 1H), 8.25(s, 1H), 6.58 (s, 1H), 4.30 (d, J = 5.5 Hz, 2H), 3.66 - 3.61 (m, 4H),3.36 - 3.24 (m, 4H), 2.57 (s, 3H), 1.36 (s, 3H), 0.63 (d, J = 6.5 Hz,4H). [M+H] = 342.0.

Example 741.6-Methyl-N-(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 - 8.74 (m, 1H), 8.37 (s, 1H), 8.26 (s,2H), 4.44 (d, J = 5.9 Hz, 2H), 3.77 (s, 3H), 2.63 - 2.52 (m, 3H), 1.42 -1.33 (m, 3H), 0.69 - 0.61 (m, 4H). [M+H] = 341.97.

Example 742.5-{3-Bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (d, J = 10.1 Hz, 1H), 8.30 (s, 1H),8.14 - 7.89 (m, 1H), 7.21 (br s, 1H), 4.96 - 4.63 (m, 4H), 2.48 (s, 3H),1.34 (s, 3H), 0.60 (br s, 4H). [M+H] = 429.7.

Example 743.6-Methyl-N-[(2-methyl-1,3-thiazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (t, J = 5.7 Hz, 1H), 8.39 (s, 1H), 8.27(s, 1H), 7.51 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 2.53 (d, J = 12.5 Hz,6H), 1.38 (s, 3H), 0.68 (d, J = 3.4 Hz, 4H). [M+H] = 358.0.

Example 744.6-Methyl-N-[(2-methyl-1,3-oxazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (t, J = 5.6 Hz, 1H), 8.45 (s, 1H), 8.29(s, 1H), 6.87 (s, 1H), 4.45 (d, J = 5.5 Hz, 2H), 2.53 (s, 3H), 2.32 (s,3H), 1.38 (s, 3H), 0.67 (d, J = 4.5 Hz, 4H). [M+H] = 342.1.

Example 745.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(morpholin-4-yl)pyridazin-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.89 - 8.80 (m, 1H), 8.39 (br s, 1H), 8.27(s, 1H), 7.85 - 7.74 (m, 1H), 4.59 (d, J = 5.6 Hz, 3H), 3.74 - 3.67 (m,3H), 3.60 (d, J = 4.9 Hz, 5H), 2.60 (d, J = 2.1 Hz, 3H), 1.42 - 1.34 (m,3H), 0.70 - 0.57 (m, 4H). [M+H] = 424.0.

Example 746.N-(Cyclopropylmethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 6.41 - 6.32 (m, 1H), 3.30 - 3.21(m, 2H), 2.73 (s, 4H), 1.49 - 1.43 (m, 3H), 1.11 - 0.82 (m, 5H), 0.64 -0.43 (m, 2H), 0.35 - 0.14 (m, 2H). [M+H] = 301.2.

Example 747.6-Methyl-N-[(2-methyl-1,3-oxazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) 6 8.34 (s, 1H), 7.66 (s, 1H), 4.82 (br s, 2H),4.39 (d, J = 0.9 Hz, 2H), 2.63 (s, 3H), 2.35 (s, 3H), 1.43 (s, 3H),0.99 - 0.83 (m, 4H). [M+H] = 342.2.

Example 748.6-Methyl-N-(1-methylcyclopropyl)-5-[3-(oxan-4-yl)-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.57 - 8.48 (m, 1H), 8.47 (s, 1H), 8.13 - 7.95(m, 1H), 5.15 (br s, 2H), 5.01 (d, J = 13.6 Hz, 2H), 4.06 (d, J = 11.4Hz, 2H), 3.67 - 3.52 (m, 2H), 3.12 -2.95 (m, 1H), 2.68 (s, 3H), 1.82 (brs, 4H), 1.49 (s, 3H), 1.03 - 0.87 (m, 4H). [M+H] = 434.0.

Example 749.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1,3-oxazol-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 7.82 (d, J = 0.7 Hz, 1H), 7.08(d, J = 0.6 Hz, 1H), 5.30 (q, J = 7.1 Hz, 1H), 2.64 (s, 3H), 1.58 (d, J= 7.1 Hz, 3H), 1.42 (s, 3H), 0.93 - 0.82 (m, 4H). [M+H] = 342.0.

Example 750.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1,2-oxazol-3-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 1.7 Hz, 1H), 8.32 (s, 1H), 6.46(d, J = 1.7 Hz, 1H), 5.33 (q, J = 7.1 Hz, 1H), 2.63 (s, 3H), 1.55 (d, J= 7.1 Hz, 3H), 1.42 (s, 3H), 0.93 - 0.79 (m, 4H). [M+H] = 342.1.

Example 751.N-[(5-Fluoro-1,3-benzoxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H), 7.52 (dd, J = 4.2, 9.0 Hz, 1H),7.30 (dd, J = 2.5, 8.4 Hz, 1H), 7.08 (dt, J = 2.6, 9.2 Hz, 1H). [M+H] =396.0.

Example 752.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[3-(pyrrolidin-1-yl)propyl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 3.68 - 3.54 (m, 2H), 3.43 (t, J= 6.8 Hz, 2H), 3.25 - 3.17 (m, 3H), 3.07 - 2.93 (m, 2H), 2.64 (s, 3H),2.17 - 1.85 (m, 6H), 1.42 (s, 3H), 0.93 - 0.79 (m, 4H). [M+H] = 358.0.

Example 753.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(morpholin-4-yl)pyridin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J = 2.6 Hz, 1H), 8.28 (s, 1H), 8.03(d, J = 2.6 Hz, 1H), 7.27 (d, J = 9.8 Hz, 1H), 3.80 - 3.74 (m, 4H),3.59 - 3.51 (m, 4H), 2.67 (s, 3H), 1.41 (s, 3H), 0.83 - 0.73 (m, 4H).[M+H] = 409.2.

Example 754.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3,3,3-trifluoropropyl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.74 - 8.61 (m, 1H), 8.45 (s, 1H), 6.45 - 6.31(m, 1H), 3.77 (d, J = 6.2 Hz, 2H), 2.66 (s, 3H), 2.58 - 2.40 (m, 2H),1.54 (s, 3H), 0.96 - 0.73 (m, 4H). [M+H] = 343.1.

Example 755.N-[(2,2-Difluorocyclopropyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.56 - 8.46 (m, 1H), 8.36 (s, 1H), 6.28 - 6.11(m, 1H), 3.93 - 3.79 (m, 1H), 3.30 - 3.16 (m, 1H), 2.58 (s, 3H), 2.03 -1.83 (m, 1H), 1.50 - 1.43 (m, 3H), 1.30 -1.07 (m, 2H), 0.86 - 0.60 (m,4H). [M+H] = 337.1.

Example 756.N-(2-{[Dimethyl(oxo)-λ⁶-sulfanylidene]amino}ethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) δ 8.41 - 8.20 (m, 1H), 3.66 (s, 6H), 3.55 (dd, J= 5.3, 11.9 Hz, 4H), 3.21 (s, 2H), 2.65 (s, 3H), 1.42 (s, 3H), 0.95 -0.78 (m, 4H). [M+H] = 366.1.

Example 757.6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyrimidin-5-yl)furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.51 - 8.28 (m, 3H), 4.46 - 4.32 (m, 2H),4.25 - 4.05 (m, 2H), 3.20 - 3.06 (m, 2H), 2.73 (br s, 3H), 1.93 - 1.87(m, 2H), 1.73 - 1.64 (m, 2H), 1.42 (s, 3H), 0.84 - 0.66 (m, 4H). [M+H] =436.3.

Example 758.N-[2-(3,3-Dimethylmorpholin-4-yl)pyrimidin-5-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.63 - 8.54 (m, 2H), 8.48 - 8.41 (m, 1H),3.94 - 3.79 (m, 4H), 3.54 - 3.45 (m, 2H), 2.78 (s, 3H), 1.54 - 1.50 (m,9H), 0.88 - 0.75 (m, 4H). [M+H] = 438.28.

Example 759.N-{2-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyrimidin-5-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 2H), 8.53 (s, 1H), 4.53 (d, J = 12.1Hz, 2H), 3.73 -3.62 (m, 2H), 2.82 (s, 3H), 2.74 (dd, J = 10.8, 13.3 Hz,2H), 1.50 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H), 1.04 - 0.92 (m, 4H). [M+H]= 438.

Example 760.6-Methyl-N-[(4-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) b 8.43 (s, 1H), 7.60 (d, J = 1.3 Hz, 1H), 4.69(s, 2H), 2.77 (s, 3H), 2.15 (d, J = 1.3 Hz, 3H), 1.52 (s, 3H), 1.06 -0.90 (m, 4H). [M+H] = 342.1.

Example 761 was prepared in a manner analogous to Example 3, with theappropriate starting material substitutions.

Example 761.6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, DMSO-d₆) d = 8.73 (s, 1H), 8.35 - 8.24 (m, 1H), 7.90(br s, 1H), 7.73 (br s, 1H), 2.62 (s, 3H), 1.45 (s, 3H), 0.76 - 0.65 (m,4H). [M+H] = 247.

Example 762 was prepared in a manner analogous to Example 7, with theappropriate starting material substitutions.

Example 762.6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) b 8.62 (s, 1H), 8.37 (s, 1H), 4.83 (br s, 2H),4.72 - 4.62 (m, 1H), 4.15 - 3.70 (m, 2H), 2.67 (t, J = 5.3 Hz, 2H),2.60 - 2.55 (m, 3H), 1.47 (s, 3H), 1.32 (d, J = 6.6 Hz, 6H), 0.85 - 0.79(m, 4H). [M+H] = 421.99.

Example 763 - Example 773 were prepared in a manner analogous to Example11, with the appropriate starting material substitutions.

Example 763.5-[4-(Fluoromethoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.61 (d, J = 6.4 Hz, 1H), 8.38 (s, 1H), 7.52(d, J = 6.5 Hz, 1H), 6.17 - 5.96 (m, 2H), 5.06 (br s, 2H), 4.27 - 3.69(m, 2H), 3.03 - 2.96 (m, 2H), 2.59 (s, 3H), 1.47 (s, 3H), 0.89 - 0.79(m, 4H). [M+H] = 412.20.

Example 764.5-[5-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) b 8.35 (s, 1H), 7.26 - 7.16 (m, 1H), 7.03 (d, J= 8.1 Hz, 1H), 6.93 (br s, 1H), 5.87 - 5.69 (m, 2H), 4.97 - 4.84 (m,2H), 3.93 (br s, 2H), 2.93 (br s, 2H), 2.52 (s, 3H), 1.44 (s, 3H), 0.79(s, 4H). [M+H] = 411.04.

Example 765.5-[6-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.13 (br s, 1H), 7.00 - 6.89 (m,2H), 5.85 -5.61 (m, 2H), 4.79 (br s, 2H), 3.92 (br s, 2H), 2.98 (br s,2H), 2.53 (s, 3H), 1.46 (s, 3H), 0.82 (br s, 4H). [M+H] = 411.05.

Example 766.5-[8-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.30 - 7.20 (m, 1H), 7.03 (d, J= 7.9 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 5.90 - 5.67 (m, 2H), 4.80 (brs, 2H), 3.93 (br s, 2H), 2.99 (br s, 2H), 2.53 (s, 3H), 1.46 (s, 3H),0.82 (d, J = 4.6 Hz, 4H). [M+H] = 411.06.

Example 767.5-[7-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.01 -6.87 (m, 2H), 5.80 - 5.61 (m, 2H), 4.84 - 4.69 (m, 2H), 3.92 (br s, 2H),2.95 (br s, 2H), 2.55 (s, 3H), 1.47 (s, 3H), 0.83 (br s, 4H). [M+H] =411.06.

Example 768.5-[3-(Fluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.67(br s, 1H), 5.96 - 5.74 (m, 2H), 4.97 (br s, 2H), 4.08 (d, J = 13.3 Hz,2H), 3.13 (t, J = 5.4 Hz, 2H), 2.60 (s, 3H), 1.49 (s, 3H), 0.86 (s, 4H).[M+H] = 412.06.

Example 769.5-[5-(Fluoromethoxy)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 8.00 (d, J = 5.3 Hz, 1H), 6.96(br s, 1H), 6.21 - 5.97 (m, 2H), 5.02 - 4.90 (m, 2H), 4.14 - 3.75 (m,2H), 2.94 - 2.82 (m, 2H), 2.58 - 2.51 (m, 3H), 1.49 - 1.43 (m, 3H), 0.84(br s, 4H). [M+H] = 412.06.

Example 770.5-{4-[5-(Fluoromethoxy)pyrimidin-2-yl]piperidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 2H), 8.40 (s, 1H), 5.98 - 5.71 (m,2H), 3.26 (tt, J = 3.8, 11.5 Hz, 1H), 2.57 (s, 3H), 2.12 (d, J = 10.4Hz, 2H), 1.92 (br s, 2H), 1.54 (s, 3H), 1.01 -0.93 (m, 2H), 0.93 - 0.84(m, 2H). [M+H] = 441.07.

Example 771.5-{3-[4-(Fluoromethoxy)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 7.40 - 7.22 (m, 2H), 7.07 (d, J= 18.1 Hz, 2H), 5.87 - 5.62 (m, 2H), 4.04 (br s, 1H), 3.86 - 3.71 (m,2H), 3.65 - 3.41 (m, 2H), 2.57 (d, J = 14.4 Hz, 3H), 2.49 - 1.99 (m,2H), 1.52 (s, 3H), 0.96 - 0.82 (m, 4H). [M+H] = 425.05.

Example 772.5-[7-(Fluoromethoxy)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.40 (s, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.08 -6.89 (m, 2H), 5.98 - 5.51 (m, 3H), 4.84 - 3.34 (m, 2H), 3.09 - 2.79 (m,2H), 2.63 - 2.48 (m, 3H), 1.57 (br s, 3H), 1.46 (br s, 3H), 0.81 (br s,4H). [M+H] = 425.10.

Example 773.5-[4-(Fluoromethoxy)-2-(methoxymethyl)-5H,6H,7H,8H-pyridor3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.41 (s, 1H), 6.29 - 6.06 (m, 2H), 4.96 - 4.86(m, 2H), 4.54 (s, 2H), 4.00 (br s, 2H), 3.48 (s, 3H), 2.88 (br s, 2H),2.62 - 2.54 (m, 3H), 1.48 (s, 3H), 0.88 (d, J = 5.0 Hz, 4H). [M+H] =457.40.

Example 774 - Example 775 were prepared in a manner analogous to Example13, with the appropriate starting material substitutions.

Example 774.5-[3-(5-Fluoropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.96 - 8.50 (m, 2H), 8.31 (s, 1H), 7.14 - 6.70(m, 1H), 2.60 (br s, 3H), 1.48 (s, 3H), 0.91 - 0.66 (m, 4H). [M+H] =395.0.

Example 775.2-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-4-carbonitrile

¹H NMR (400 MHz, CD₃OD) δ 9.17 - 8.84 (m, 1H), 8.36 (s, 1H), 7.83 - 7.60(m, 1H), 4.47 (br s, 1H), 3.91 (br s, 2H), 2.85 (br s, 1H), 2.59 - 2.52(m, 3H), 2.52 - 2.26 (m, 1H), 1.51 -1.47 (m, 3H), 0.93 - 0.77 (m, 4H).[M+H] = 416.05.

Example 776 - Example 782 were prepared in a manner analogous to Example14, with the appropriate starting material substitutions.

Example 776.6-Methyl-5-[4-(1-methyl-1H-pyrazol-3-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 6.13(br s, 1H), 4.80 - 3.90 (m, 2H), 3.85 (s, 3H), 3.39 - 3.08 (m, 6H), 3.00(t, J = 11.4 Hz, 1H), 2.52 (s, 3H), 2.14 - 1.95 (m, 2H), 1.91 - 1.61 (m,2H), 1.51 (s, 3H), 0.91 - 0.71 (m, 4H). [M+H] = 395.1.

Example 777.6-Methyl-5-[4-(1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 8.43 (s, 1H), 4.77 - 3.98 (m,2H), 3.92 (s, 3H), 3.33 (td, J = 1.6, 3.2 Hz, 4H), 3.15 (tt, J = 3.7,11.1 Hz, 1H), 2.58 (s, 3H), 2.22 - 2.04 (m, 2H), 1.86 (br s, 2H), 1.54(s, 3H), 1.03 - 0.85 (m, 4H). [M+H] = 396.1.

Example 778.6-Methyl-5-[4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.79 (s, 1H), 4.78 - 4.12 (m,2H), 4.09 (s, 3H), 3.50 (d, J = 1.7 Hz, 1H), 3.29 - 3.20 (m, 1H), 3.13(tt, J = 3.7, 11.5 Hz, 1H), 2.58 (s, 3H), 2.22 - 2.06 (m, 2H), 1.92 -1.67 (m, 2H), 1.54 (s, 3H), 1.04 - 0.85 (m, 4H). [M+H] = 396.1.

Example 779.5-[4-(1,5-Dimethyl-1H-pyrazol-3-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 6.01 (s, 1H), 4.76 - 3.84 (m,2H), 3.76 (s, 3H), 3.57 - 3.07 (m, 10H), 3.02 - 2.90 (m, 1H), 2.57 (s,3H), 2.29 (s, 3H), 2.04 (d, J = 11.6 Hz, 2H), 1.70 (d, J = 7.8 Hz, 2H),1.54 (s, 3H), 1.05 - 0.82 (m, 4H). [M+H] = 409.1.

Example 780.5-[4-(2,4-Dimethyl-1H-imidazol-5-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 4.78 - 3.85 (m, 1H), 3.65 - 3.28(m, 16H), 3.58 - 3.23 (m, 16H), 3.16 (t, J = 12.2 Hz, 2H), 2.58 (br s,3H), 2.57 (s, 4H), 2.31 (s, 3H), 1.95 (br s, 2H), 1.87 - 1.64 (m, 2H),1.53 (s, 3H), 0.97 - 0.78 (m, 5H). [M+H] = 409.1.

Example 781.6-Methyl-N-(1-methylcyclopropyl)-5-{4-[1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.58 (d, J = 2.3 Hz, 1H), 6.15(d, J = 2.1 Hz, 1H), 4.49 (quind, J = 6.7, 13.4 Hz, 1H), 4.39 - 3.73 (m,1H), 3.56 - 3.11 (m, 11H), 3.10 -2.95 (m, 1H), 2.58 (s, 3H), 2.12 - 1.97(m, 2H), 1.89 - 1.64 (m, 2H), 1.54 (s, 3H), 1.48 (d, J = 6.7 Hz, 6H),1.10 - 0.84 (m, 4H). [M+H] = 423.2.

Example 782.6-Methyl-5-[4-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.50 (s, 1H), 7.40 (s, 1H),4.76 - 3.91 (m, 2H), 3.86 (s, 3H), 3.48 - 3.03 (m, 9H), 2.98 - 2.82 (m,1H), 2.57 (s, 3H), 2.16 - 2.00 (m, 2H), 1.63 (br s, 2H), 1.53 (s, 3H),1.01 - 0.80 (m, 4H). [M+H] = 395.2.

Example 783 - Example 785 were prepared in a manner analogous to Example15, with the appropriate starting material substitutions.

Example 783.5-[4-(2-Fluoro-1,3-thiazol-5-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 7.23 (s, 1H), 6.08 (br s, 1H),4.32 (br s, 2H), 4.09 - 3.61 (m, 2H), 2.66 (br s, 2H), 2.53 (s, 3H),1.48 (s, 3H), 0.85 - 0.66 (m, 4H). [M+H] = 414.0.

Example 784,5-[4-(5-Methoxypyrazin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.38 (s, 1H), 8.32 (d, J = 1.1 Hz, 1H), 8.18(d, J = 1.2 Hz, 1H), 6.63 (br s, 1H), 4.40 (br s, 2H), 4.08 - 3.82 (m,5H), 2.78 (br s, 2H), 2.57 (s, 3H), 1.50 (s, 3H), 0.94 - 0.76 (m, 4H).[M+H] = 421.1.

Example 785.5-[4-(5-Methoxypyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.31 (s, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.52(d, J = 8.8 Hz, 1H), 7.37 (dd, J = 3.0, 8.9 Hz, 1H), 6.48 (br s, 1H),4.36 (br s, 2H), 3.88 (s, 4H), 2.76 (br s, 2H), 2.53 (s, 3H), 1.46 (s,3H), 0.86 - 0.64 (m, 4H). [M+H] = 420.1.

Example 786 - Example 796 were prepared in a manner analogous to Example18, with the appropriate starting material substitutions.

Example 786.5-{4-[(3S)-3-Fluoropyrrolidin-1-yl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1H), 8.37 (s, 1H), 5.53 - 5.30 (m,1H), 5.01 (br s, 1H), 4.74 (d, J = 18.0 Hz, 1H), 4.36 - 3.99 (m, 5H),3.62 (br s, 1H), 3.27 (br s, 1H), 3.21 - 3.09 (m, 1H), 2.61 (s, 3H),2.42 (dt, J = 6.4, 15.2 Hz, 1H), 2.33 - 2.08 (m, 1H), 1.50 (s, 3H), 0.91-0.78 (m, 4H). [M+H] = 452.01.

Example 787.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(morpholin-4-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.63 (s, 1H), 8.38 (s, 1H), 4.89 (br s, 2H),4.06 - 3.72 (m, 10H), 2.94 (br s, 2H), 2.61 (s, 3H), 1.50 (s, 3H),0.94 - 0.77 (m, 4H). [M+H] = 450.07.

Example 788.5-[4-(3-Fluoroazetidin-1-yl)-5H,6H,7H,8H-pyrido[3,4-dlpyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H), 8.37 (s, 1H), 5.65 - 5.35 (m,1H), 5.01 -4.89 (m, 2H), 4.87 - 4.82 (m, 2H), 4.75 - 4.57 (m, 2H), 3.94(br s, 2H), 2.97 (t, J = 5.2 Hz, 2H), 2.59 (s, 3H), 1.50 (s, 3H), 0.93 -0.77 (m, 4H). [M+H] = 438.08.

Example 789.5-{2-Chloro-4-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 4.55 (br s, 2H), 4.37 (td, J =6.5, 13.1 Hz, 1H), 4.10 - 3.62 (m, 2H), 2.58 - 2.51 (m, 2H), 2.50 (s,3H), 1.43 (s, 3H), 1.24 (d, J = 6.5 Hz, 6H), 0.71 (br s, 4H). [M+H] =456.04.

Example 790.5-{4-[Cyclopropyl(methyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 1H), 8.36 (s, 1H), 4.91 (br s, 2H),3.86 (br s, 2H), 3.35 (s, 4H), 3.25 (br s, 2H), 2.68 - 2.56 (m, 3H),1.51 (s, 3H), 1.06 - 0.94 (m, 2H), 0.94 - 0.76 (m, 6H). [M+H] = 434.11.

Example 791.5-[4-(Dimethylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.37 (s, 1H), 3.88 (br s, 2H),3.43 (s, 6H), 3.11 (br s, 2H), 2.69 - 2.54 (m, 3H), 1.51 (s, 3H), 0.91 -0.76 (m, 4H). [M+H] = 408.05.

Example 792,6-Methyl-5-[4-(methylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.36 (s, 1H), 4.86 - 4.80 (m,2H), 4.02 (br s, 2H), 3.18 (s, 3H), 2.66 (br s, 2H), 2.59 (s, 3H), 1.49(s, 3H), 0.82 (d, J = 10.9 Hz, 4H). [M+H] = 394.02.

Example 793.6-Methyl-5-{4-[methyl(oxan-4-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.37 (s, 1H), 4.96 - 4.89 (m,2H), 4.83 (br s, 1H), 4.07 (dd, J = 4.3, 11.4 Hz, 2H), 4.01 - 3.69 (m,2H), 3.64 - 3.50 (m, 2H), 3.26 (s, 3H), 3.06 (br s, 2H), 2.61 (s, 3H),2.03 (dq, J = 4.5, 12.2 Hz, 2H), 1.78 (dd, J = 2.1, 12.1 Hz, 2H), 1.51(s, 3H), 0.92 - 0.77 (m, 4H). [M+H] = 478.05.

Example 794.6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(oxan-4-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1H), 8.37 (s, 1H), 5.00 - 4.88 (m,2H), 4.67 -4.51 (m, 1H), 4.24 - 3.84 (m, 4H), 3.61 - 3.47 (m, 2H), 2.70(br s, 2H), 2.60 (s, 3H), 1.99 - 1.88 (m, 2H), 1.80 (dq, J = 4.5, 12.2Hz, 2H), 1.49 (s, 3H), 0.82 (d, J = 6.0 Hz, 4H). [M+H] = 464.05.

Example 795.5-(4-{[1-(Methoxymethyl)cyclopropyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.36 (s, 1H), 4.20 - 3.76 (m,2H), 3.61 (s, 2H), 3.37 (s, 3H), 2.66 (br s, 2H), 2.59 (s, 3H), 1.54 -1.42 (m, 3H), 1.09 - 0.94 (m, 4H), 0.81 (d, J = 6.8 Hz, 4H). [M+H] =463.99.

Example 796.6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(1-methylcyclopropyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 8.37 (s, 1H), 4.87 - 4.78 (m,2H), 3.98 (br s, 2H), 2.63 (br s, 2H), 2.59 (s, 3H), 1.50 (d, J = 9.7Hz, 6H), 1.01 - 0.75 (m, 8H). [M+H] = 434.09.

Example 797 was prepared in a manner analogous to Example 20, with theappropriate starting material substitutions.

Example 797.5-{3-[4-(2-Fluoroethoxy)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.38 - 7.15 (m, 2H), 7.02 - 6.87(m, 2H), 4.84 - 4.59 (m, 2H), 4.33 - 4.11 (m, 2H), 4.05 - 3.40 (m, 5H),2.58 (d, J = 14.9 Hz, 3H), 2.46 -2.00 (m, 2H), 1.53 (s, 3H), 0.98 - 0.84(m, 4H). [M+H] = 439.02.

Example 798 - Example 802 were prepared in a manner analogous to Example21, with the appropriate starting material substitutions.

Example 798.5-[3-(6-Fluoro-4-methylpyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.39 (s, 1H), 7.24 - 7.03 (m, 1H), 6.89 - 6.68(m, 1H), 4.05 - 3.49 (m, 5H), 2.60 (d, J = 6.8 Hz, 3H), 2.50 - 2.12 (m,5H), 1.53 (s, 3H), 1.02 - 0.82 (m, 4H). [M+H] = 410.11.

Example 799.5-[3-(5-Fluoro-6-methylpyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 7.63 - 7.41 (m, 1H), 7.41 - 7.18(m, 1H), 4.11 - 3.57 (m, 5H), 2.62 (d, J = 8.9 Hz, 3H), 2.57 - 2.13 (m,5H), 1.54 (s, 3H), 1.08 - 0.89 (m, 4H). [M+H] = 410.12.

Example 800.5-[3-(5-Fluoro-4-methylpyrimidin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.61 - 8.38 (m, 2H), 4.17 - 3.66 (m, 5H), 2.62(s, 3H), 2.59 - 2.21 (m, 5H), 1.54 (s, 3H), 1.08 - 0.88 (m, 4H). [M+H] =411.32.

Example 801.6-Methyl-N-(1-methylcyclopropyl)-5-{3-[6-(trifluoromethyl)pyridin-2-yl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.47 - 8.32 (m, 1H), 8.10 - 7.91 (m, 1H),7.80 - 7.55 (m, 2H), 4.15 - 3.67 (m, 5H), 2.65 - 2.56 (m, 3H), 2.56 -2.16 (m, 2H), 1.57 - 1.49 (m, 3H), 1.02 -0.84 (m, 4H). [M+H] = 446.53.

Example 802.6-Methyl-N-(1-methylcyclopropyl)-5-{3-[4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.92 - 8.67 (m, 1H), 8.46 - 8.34 (m, 1H),7.82 - 7.45 (m, 2H), 4.18 - 3.66 (m, 5H), 2.66 - 2.18 (m, 5H), 1.54 (s,3H), 1.03 - 0.83 (m, 4H). [M+H] = 446.31.

Example 803 was prepared in a manner analogous to Example 23, with theappropriate starting material substitutions.

Example 803.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(oxan-4-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.99 (s, 1H), 8.49 (s, 1H), 7.10 (br s, 1H),4.83 (br s, 2H), 4.09-4.19 (m, 3H), 3.57 (dt, J = 1.71, 11.92 Hz, 2H),3.03-3.16 (m, 1H), 3.00 (t, J = 5.56 Hz, 2H), 2.54 (s, 3H), 2.08-2.22(m, 2H), 1.64 (d, J = 12.96 Hz, 3H), 1.50 (s, 3H), 0.77 (br s, 4H).[M+H] = 449.4.

Example 804 - Example 805 were prepared in a manner analogous to Example24, with the appropriate starting material substitutions.

Example 804.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(prop-1-en-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 8.40 (s, 1H), 5.60 (s, 1H), 5.25(s, 1H), 4.91 (br s, 2H), 3.94 (br s, 2H), 3.10 - 2.99 (m, 2H), 2.59 (s,3H), 2.14 (s, 3H), 1.48 (s, 3H), 0.92 -0.83 (m, 4H). [M+H] = 405.42.

Example 805.5-{4-Cyclopropyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 1H), 8.41 (s, 1H), 4.84 - 4.70 (m,2H), 4.26 -3.76 (m, 2H), 3.11 (br s, 2H), 2.59 (s, 3H), 2.19 (d, J = 5.0Hz, 1H), 1.48 (s, 3H), 1.26 - 1.09 (m, 4H), 0.88 (d, J = 6.2 Hz, 4H).[M+H] = 405.42.

Example 806 - Example 811 were prepared in a manner analogous to Example25, with the appropriate starting material substitutions.

Example 806.6-Methyl-N-(1-methylcyclopropyl)-5-{4-propoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.59 (s, 1H), 8.48 (s, 1H), 7.00 (br s, 1H),4.75 (br s, 2H), 4.39 (t, J = 6.66 Hz, 2H), 3.52-4.18 (m, 2H), 2.84 (t,J = 5.01 Hz, 2H), 2.51 (s, 3H), 1.84 (sxt, J = 7.12 Hz, 2H), 1.51 (s,3H), 1.05 (t, J = 7.46 Hz, 3H), 0.71-0.82 (m, 4H). [M+H] = 423.4.

Example 807.6-Methyl-N-(1-methylcyclopropyl)-5-[4-(2-methylpropoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.59 (s, 1H), 8.48 (s, 1H), 7.00 (br s, 1H),4.75 (br s, 2H), 4.20 (d, J = 6.72 Hz, 2H), 3.53-4.13 (m, 2H), 2.78-2.88(m, 2H), 2.52 (s, 3H), 2.14 (quind, J = 6.71, 13.37 Hz, 1H), 1.51 (s,3H), 1.05 (d, J = 6.72 Hz, 6H), 0.71-0.83 (m, 4H). [M+H] = 437.4.

Example 808.5-[4-(Cyclopropylmethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-H-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.57 (s, 1H), 8.49 (s, 1H), 7.00 (br s, 1H),4.75 (br s, 2H), 4.28 (d, J = 7.09 Hz, 2H), 3.47-4.16 (m, 2H), 2.86 (t,J = 5.69 Hz, 2H), 2.52 (s, 3H), 1.51 (s, 3H), 1.26-1.37 (m, 1H),0.72-0.83 (m, 4H), 0.59-0.69 (m, 2H), 0.32-0.43 (m, 2H). [M+H] = 435.4.

Example 809.5-[4-(2-Methoxyethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDC1₃) δ 8.59 (s, 1H), 8.49 (s, 1H), 7.04 (br s, 1H),4.76 (br s, 2H), 4.57-4.63 (m, 2H), 3.80-4.33 (m, 2H), 3.78 (dd, J =3.91, 5.38 Hz, 2H), 3.45 (s, 3H), 2.88 (t, J = 5.62 Hz, 2H), 2.52 (s,3H), 1.52 (s, 3H), 0.74-0.85 (m, 4H). [M+H] = 439.4.

Example 810.5-{4-Cyclobutoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 8.48 (s, 1H), 7.00 (br s, 1H),5.32 (quin, J = 7.43 Hz, 1H), 4.74 (br s, 2H), 3.62-4.33 (m, 2H),2.82-2.86 (m, 2H), 2.48-2.58 (m, 5H), 2.13-2.27 (m, 2H), 1.83-1.96 (m,1H), 1.66-1.80 (m, 1H), 1.51 (s, 3H), 0.73-0.83 (m, 4H). [M+H] = 435.4.

Example 811.5-{4-Cyclopropoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.48 (s, 1H), 6.99 (br s, 1H),4.76 (br s, 2H), 4.45 (tt, J = 3.13, 6.22 Hz, 1H), 3.59-4.30 (m, 2H),2.77 (t, J = 5.69 Hz, 2H), 2.51 (s, 3H), 1.51 (s, 3H), 0.82-0.95 (m,4H), 0.72-0.81 (m, 4H). [M+H] = 421.4.

Example 812 was prepared in a manner analogous to Example 27, with theappropriate starting material substitutions.

Example 812.5-{2-Cyclopropyl-4-methoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CD₃OD) 5 8.35 (s, 1H), 4.76 (br s, 2H), 4.08 - 3.72 (m,5H), 2.75 (t, J = 5.4 Hz, 2H), 2.55 (s, 3H), 2.15 - 2.07 (m, 1H), 1.46(s, 3H), 1.23 - 1.05 (m, 4H), 0.80 (d, J = 4.3 Hz, 4H). [M+H] = 435.43.

Example 813 was prepared in a manner analogous to Example 28, with theappropriate starting material substitutions.

Example 813.N-Ethyl-N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide

¹H NMR (400 MHz, CD₃OD) 5 8.85 (br s, 1H), 8.32 (br s, 1H), 7.80 (br s,1H), 6.91 (br s, 1H), 4.83 - 4.59 (m, 2H), 4.02 (br s, 3H), 3.46 (br s,2H), 2.48 (s, 3H), 1.55 (s, 3H), 1.12 (br s, 3H), 0.82 (br s, 4H). [M+H]= 397.40.

Example 814 was prepared in a manner analogous to Example 29, with theappropriate starting material substitutions.

Example 814.5-[1,3-Dimethyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine

¹H NMR (400 MHz, CDCI3) 6 8.50 (s, 1H), 6.99 (s, 1H), 4.76 (s, 2H),4.14 - 3.95 (m, 4H), 2.51 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H), 1.53 (s,3H), 0.86 - 0.80 (m, 2H), 0.79 - 0.72 (m, 2H). [M+H] = 381.3.

PHARMACOLOGICAL EXAMPLES

The present disclosure will be further illustrated by the followingpharmacological examples. These examples are understood to be exemplaryonly and are not intended to limit the scope of the invention disclosedherein.

Enzymatic Assay

PDE1B inhibition was determined by an IMAP TR-FRET assay. The IMAPTR-FRET PDE assay was optimized for concentration of enzyme, Calmodulin,cAMP or cGMP substrate, DMSO tolerance, and incubation time.

Into each well of a solid white 1536 well plate (Corning) was dispensed250 pg full-length recombinant NH-terminal GST tagged human PDE1B enzyme(BPS Bioscience Cat # 60011, San Diego, CA) in 2.5 µL IMAP BSA reactionbuffer (Molecular Devices, Sunnyvale, CA) containing 10 U/ml Calmodulinand 2.5 mM CaC12 (Sigma Aldrich.) After a brief centrifugation, 30 nL ofcompound was added by transfer from 1 mM stock in DMSO using a Kalypsys1536 Pintool. Plates were incubated for 5 minutes at room temperaturebefore dispensing 1.5 µL of 533 nM 5-carboxy fluorescein (FAM)-labeledcAMP (Molecular Devices, Sunnyvale, CA) for a final concentration of 200nM. After a brief centrifugation, the plates were incubated for 30minutes at room temperature. The assay was terminated by adding 5 µLIMAP binding reagent/Tb complex (Molecular Devices, Sunnyvale, CA) toeach well.

Plates were incubated for 1 hour at room temperature and were read on aViewlux multimode plate reader (Perkin Elmer). The instrument was set toexcite using the DUG11 filter and measure using 490/10 nm and 520/10 nmfilters. Ratios of acceptor and donor were then calculated.

Data Analysis

For IC₅₀ calculations, the values of % efficacy versus a series ofcompound concentrations were then plotted using non-linear regressionanalysis of sigmoidal dose-response curves generated with the equationY=[B+(T-B)]/[1+10((LogEC₅₀-X)×Hill Slope)], where Y = percent activity,B = minimum percent efficacy, T = maximum percent efficacy, X =logarithm of compound and Hill Slope = slope factor or Hill coefficient.The IC₅₀ value was determined by the concentration causing ahalf-maximal percent efficacy.

Results

Table 2 presents the negative log of the half-maximal molar inhibitoryconcentration (_(P)IC₅₀), with respect to PDE1B activity, for Formula Icompounds.

TABLE 2 PDElb (pICso) Example Numbers >8 1, 11, 12, 13, 14, 20, 21, 25,26, 27, 41, 42, 43, 44, 47, 51, 54, 55, 56, 57, 59, 60, 61, 62, 63, 66,67, 69, 85, 88, 101, 103, 122, 131, 132, 133, 135, 145, 147, 150, 152,154, 185, 194, 196, 209, 217, 237, 238, 267, 270, 296, 298, 301, 304,306, 309, 312, 322, 323, 329, 334, 335, 338, 340, 341, 343, 344, 345,346, 348, 351, 354, 355, 360, 361, 365, 366, 367, 368, 369, 370, 372,373, 382, 384, 385, 387, 388, 389, 390, 395, 396, 397, 398, 422, 450,454, 460, 464, 467, 475, 481, 483, 488, 493, 502, 532, 533, 536, 556,557, 559, 560, 572, 574, 585, 590, 614, 648, 649, 666, 667, 686, 698,704, 705, 708, 714, 716, 743, 751, 762, 763, 764, 765, 772, 775, 776,779, 783, 784, 785, 789, 798, 799, 800, 801, 802, 807, 808, 810, 812 7-82, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 22, 23, 28, 30, 31, 32, 33,34, 35, 38, 39, 40, 45, 48, 49, 50, 52, 53, 58, 64, 68, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 82, 86, 87, 89, 91, 92, 93, 96, 97, 98, 99, 100,102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 116, 118,124, 125, 126, 129, 130, 136, 137, 138, 139, 140, 141, 142, 143, 144,146, 148, 149, 151, 153, 155, 156, 160, 161, 162, 163, 164, 165, 167,168, 169, 170, 175, 176, 177, 178, 180, 181, 184, 186, 188, 190, 191,192, 195, 198, 203, 204, 207, 208, 210, 211, 212, 213, 218, 220, 222,223, 224, 225, 230, 233, 235, 236, 239, 244, 246, 248, 249, 250, 251,253, 254, 256, 262, 263, 265, 269, 271, 273, 274, 275, 278, 279, 280,281, 282, 283, 284, 285, 286, 287, 289, 290, 291, 292, 293, 294, 295,297, 299, 300, 302, 305, 307, 308, 311, 313, 314, 315, 317, 318, 319,320, 321, 324, 325, 326, 327, 328, 330, 331, 332, 336, 337, 339, 342,347, 349, 350, 352, 353, 356, 357, 358, 359, 362, 364, 371, 374, 377,380, 381, 383, 386, 391, 392, 393, 394, 399, 400, 401, 402, 404, 407,409, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 423, 424,426, 429, 430, 431, 432, 433, 436, 440, 441, 442, 443, 444, 445, 446,447, 448, 449, 451, 452, 453, 455, 456, 457, 458, 459, 461, 463, 465,466, 468, 471, 472, 473, 480, 482, 484, 487, 489, 495, 498, 508, 509,510, 513, 520, 521, 522, 524, 525, 528, 529, 530, 534, 545, 547, 551,552, 558, 568, 569, 570, 571, 573, 580, 584, 589, 595, 600, 604, 606,613, 615, 619, 620, 621, 623, 624, 625, 626, 627, 628, 630, 632, 634,635, 642, 644, 645, 646, 650, 651, 652, 653, 654, 655, 657, 658, 659,660, 661, 662, 664, 665, 668, 669, 673, 674, 675, 676, 677, 678, 679,680, 683, 687, 688, 689, 690, 691, 694, 695, 696, 697, 700, 702, 703,706, 707, 710, 711, 712, 713, 715, 717, 718, 719, 722, 723, 724, 725,726, 727, 728, 729, 730, 731, 732, 733, 734, 736, 737, 738, 739, 740,741, 742, 744, 745, 746, 747, 750, 754, 755, 757, 758, 760, 766, 767,768, 769, 770, 771, 773, 774, 777, 778, 781, 782, 786, 787, 788, 790,791, 792, 793, 794, 795, 796, 797, 803, 804, 805, 806, 809, 811 6-7 19,24, 29, 36, 37, 46, 65, 80, 81, 83, 90, 94, 95, 115, 117, 119, 120, 121,123, 127, 128, 134, 157, 158, 159, 171, 174, 189, 214, 215, 260, 288,303, 310, 316, 333, 363, 375, 376, 378, 379, 403, 405, 406, 408, 410,425, 427, 428, 434, 435, 437, 438, 439, 462, 469, 470, 499, 518, 575,583, 622, 629, 631, 633, 636, 637, 638, 639, 640, 641, 643, 647, 656,663, 670, 671, 672, 681, 682, 684, 685, 692, 693, 699, 701, 709, 720,721, 735, 748, 749, 753, 756, 759, 761, 780, 813, 814 <6 193, 752

PDE1 SELECTIVITY OF COMPOUNDS Assay Conditions

The selectivity of compounds of the present invention was determinedusing a panel of recombinant human PDEs and an in vitro enzymatic assay(BPS Bioscience). A series of dilutions of each test compound wereprepared with 10% DMSO in assay buffer and 5 µL of the dilution wasadded to a 50 µL reaction so that the final concentration of DMSO is 1%in all of reactions.

The enzymatic reactions were conducted at room temperature for 60minutes in a 50 µL mixture containing PDE assay buffer, 100 nM FAM-cAMP,or 100 nM FAM-cGMP, a recombinant PDE enzyme and the test compound.

After the enzymatic reaction, 100 µL of a binding solution (1: 100dilution of the binding agent with the binding agent diluent) was addedto each reaction and the reaction was performed at room temperature for60 minutes.

Fluorescence intensity was measured at an excitation of 485 nm and anemission of 528 nm using a Tecan Infinite M1000 microplate reader.

Data Analysis

PDE activity assays were performed in duplicate at each concentration.Fluorescence intensity is converted to fluorescence polarization usingthe Tecan Magellan6 software. The fluorescence polarization data wereanalyzed using the computer software, Graphpad Prism. The fluorescencepolarization (FPt) in absence of the compound in each data set wasdefined as 100% activity. In the absence of PDE and the compound, thevalue of fluorescent polarization (FPb) in each data set was defined as0% activity. The percent activity in the presence of the compound wascalculated according to the following equation: % activity =(FP-FPb)/(FPt-FPb)×100%, where FP= the fluorescence polarization in thepresence of the compound. For IC₅₀ calculations, the values of %activity versus a series of compound concentrations were then plottedusing non-linear regression analysis of Sigmoidal dose-response curvegenerated with the equation Y=[B+(T-B)]/[1+10((LogEC₅₀-X)×Hill Slope)],where Y=percent activity, B=minimum percent activity, T=maximum percentactivity, X=logarithm of compound and Hill Slope=slope factor or Hillcoefficient. The IC₅₀ value was determined by the concentration causinga half-maximal percent activity.

Results

Exemplary compounds of the present invention displayed selectivity forPDE1 enzymes versus isoforms from many, if not all, other PDE families.In addition, exemplary compounds showed greater specificity for PDE1Bcompared to PDE1A and PDE1C.

BIOLOGICAL EXAMPLES

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary only,and not to limit the scope of the invention disclosed herein.

Biological Example 1 Effect of Exemplary Compounds on Memory andCatalepsy

The studies here evaluated the effect of exemplary compounds of thepresent invention on memory and haloperidol induced catalepsy in miceand rats.

Methods Subjects

Outbred hooded Long Evans rats (400 g average weight, sourced fromTaconic Farms or Envigo) were used for rat fear conditioning, objectrecognition, and catalepsy. Upon arrival, rats were house in standardcages in groups of two. Experiments were always conducted during thelight phase of the cycle. The animals received food and water ad libitumexcept during training and testing. All procedures were consistent withNational Institutes of Health (NIH) guidelines and approved by theDNS/Helicon Institutional Animal Care and Use Committee.

Drug Administration

PDE1 inhibitors and positive control were dosed in a vehicle containing10% NMP, 40% PEG (MW400) and 50% water, unless specified otherwise. Forsubcutaneous dosing (s.c.), all drugs were administered at a volume of10 mL per kg 30 min prior to behavior training unless specifiedotherwise. For oral dosing (p.o.), animals were dosed at the indicatedamount 60 minutes prior to training.

Fear Conditioning Rationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. See, e.g.,Fanselow, 1984, Behav. Neurosci. 98, 269-277; Fanselow, 1984, Behav.Neurosci. 98, 79-95; Phillips and LeDoux, 1992, Behav. Neurosci. 106,274-285.

Contextual conditioning has been used to investigate the neuralsubstrates mediating fear-motivated learning. See, e.g., Phillips andLeDoux, 1992, Behav. Neurosci. 106, 274-285; Kim et al., 1993, Behav.Neurosci. 107, 1093-1098. Studies in mice and rats have providedevidence for functional interaction between hippocampal andnon-hippocampal systems during contextual conditioning training. See,e.g., Maren et al., 1997, Behav. Brain Res. 88, 261-274; Maren et al.,1997, Neurobiol. Learn. Mem. 67, 142-149; Frankland et al., 1998, Behav.Neurosci. 112, 863-874. Specifically, post-training lesions of thehippocampus (but not pre-training lesions) greatly reduced contextualfear, implying that: 1) the hippocampus is essential for contextualmemory but not for contextual learning per se and 2) in the absence ofthe hippocampus during training, non-hippocampal systems can supportcontextual conditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning and memory andstrain differences in mice. See, e.g., Bourtchouladze et al., 1994, Cell79, 59-68; Bourtchouladze et al., 1998, Learn Mem. 5, 365-374; Kogan etal., 1997, Current Biology 7, 1-11; Silva et al., 1996, Current Biology6, 1509-1518; Abel et al., 1997, Cell 88, 615-626; Giese et al., 1998,Science 279, 870-873; Logue et al., 1997, Neuroscience 80, 1075-1086;Chen et al., 1996, Behav. Neurosci. 110, 1177-1180; Nguyen et al., 2000,Learn Mem. 7, 170-179.

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory.See, e.g., Kim et al., 1993, Behav. Neurosci. 107, 1093-1098; Abel etal., 1997, Cell 88, 615-626; Bourtchouladze et al., 1994, Cell 79,59-68; Bourtchouladze et al., 1998, Learn. Mem. 5, 365-374. As such,contextual conditioning provides an excellent model to evaluate the roleof various novel genes in hippocampal-dependent memory formation.

Protocol

Previous investigations had established that training with 1× or 2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice. See,e.g., U.S.2009/0053140; Tully et al., 2003, Nat. Rev. Drug Discov. 2,267-77; Bourtchouladze et al., 1998, Learn. Mem. 5, 365-374.Accordingly, contextual conditioning in this study was performed asdescribed by Bourtchouladze et al., 1994, Cell 79, 59-68.

An automated fear conditioning system (Colburn Instruments) was used forcontextual conditioning and a manual setup (Med Associates) for tracefear conditioning. Rats were placed in the conditioning chamber andallowed to explore for 2 min. A total of two foot-shocks were delivered(0.4-0.6 mA, 2 s duration) with an inter-trial interval of 1 min. Thesetraining conditions generate sub-maximal, or weak, memory in controlrats, thereby allowing one to evaluate whether a PDElb compound of thepresent invention can enhance memory formation.

Freezing was scored for 30 s after the last foot-shock (immediatefreezing). Freezing was scored for 30 s after the last foot-shock(immediate freezing). The rats were then returned to their home-cage.Memory was tested after 24 h (LTM) for 3 min by scoring freezingbehavior using automated algorithms (Med Associates).

Object Recognition Memory Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, which takes advantage of the spontaneous preference ofrodents to investigate a novel object compared with a familiar one.

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. Object recognition is an ethologicallyrelevant task that does not result from negative reinforcement (footshock). This task relies on the natural curiosity of rodents to explorenovel objects in their environments more than familiar ones. Obviously,for an object to be “familiar,” the animal must have attended to itbefore and remembered that experience. Hence, animals with better memorywill attend and explore a new object more than an object familiar tothem. During testing, the animal is presented with the training objectand a second, novel one. Memory of the training object renders itfamiliar to the animal, and it then spends more time exploring the newnovel object rather than the familiar one. See Bourtchouladze et al.,2003, Proc. Natl. Acad. Sci. USA 100, 10518-10522).

Studies indicate that the NOR procedure involves several brain regions,including the cortex and the hippocampus. Recent neuroimaging studies inhumans demonstrated that memory in object recognition depends onprefrontal cortex (PFC). See Delbert et al., 1999, Neurology 52,1413-1417. Consistent with these findings, rats with the PFC lesionsshow poor working memory when they are required to discriminate betweenfamiliar and novel objects. See Mitchell, 1998, Behav. Brain Res. 97,107-113. Other studies on monkeys and rodents suggest that thehippocampus is important for novel object recognition. See, e.g., Tenget al., 2000, J. Neurosci 20, 3853-3863; Mumby, 2001, Brain Res. 127,159-181. Hence, object recognition provides an excellent behavioralmodel to evaluate drug-compound effects on cognitive task associatedwith function of the hippocampus and cortex.

Protocol

The novel object recognition task was performed as described by Bevinsand Besheer, (2006, Nat. Protocol. 1, 1306-1311) using a standard novelobject recognition system for rats (Stoelting). Objects were placed inthe center of the box, testing was carried out in low light, and timeexploring objects was assessed using Ethovision Software. All videoswere reviewed by trained observers.

For two consecutive days, rats were habituated to the chamber for 5 minwith 5 min of handling immediately following exposure to the apparatus.The next day, rats treated with 10% NMP, 40% PEG400, 50% water vehicleor drug 60 min before training were exposed to either two white blocksor two grey balls (~4 cm in width/diameter) for 3 min. Approximately 24h after training, rats were exposed to one familiar object and one novelobject (grey ball is replaced with a white block and vice versa) and thetime exploring each object was measured. Memory was scored bycalculation of a discrimination index ((T_(N)-T_(F))/(T_(N)+T_(F)))*100;between group comparison) and by comparison of the time exploring thenovel versus familiar object on the test day (within group comparison).

Catalepsy Rationale

Catalepsy in rats can be defined as a drug-induced state where theanimal may be placed in an unnatural body position and will remain inthis position for a significantly longer time than vehicle-treated rats(Wadenberg, et al., 1996, Neurosci. Biobehav. Rev., 20, 325-339). Theblockade of brain dopamine receptors by classic neurolepticantipsychotics (e.g., haloperidol) produces extrapyramidal motorside-effects (including catalepsy) in a significant proportion ofpatients (Baldessarini, et al. “Drugs and the treatment of psychiatricdisorders” The pharmacological basis of therapeutics Goodman, et al.,(eds.) New York: Pergamon Press, 383-435). The neuroleptic-inducedcataleptic state is a generally accepted animal model of the akinesiaand rigidity observed in Parkinson’s Disease (Sanberg, et al., 1998,Behavioral Neuroscience, 102, 748-759).

Protocol

Catalepsy was assessed with bar test 60 minutes after Haloperidolinjection. The fore paws of the rats were placed on a horizontal barpositioned at 10 cm above the floor. Time spent in cataleptic posture,which was defined as an immobile posture while keeping both forelimbs onthe bar, was measured with a maximum limit of 180 seconds. Automation ofcatalepsy scoring was performed using the Kinder Scientific LocoChambers and data was recorded using Kinder Scientific Motor Monitorsoftware.

Statistical Analyses

All behavioral experiments were designed and performed in a balancedfashion: (i) For each experimental condition (e.g. a specificdose-effect) an equal number of experimental and control animals wereused; (ii) Each experimental condition may be replicated several times,and (iii) Replicate days were added to generate final number ofsubjects. In each experiment, the experimenter was unaware (blind) tothe treatment of the subjects during training and testing. Data wereanalyzed by ANOVA using JMP or Prism software, followed by contrastanalysis or Dunnett’s multiple comparison tests, the results of whichare shown.

Results

Exemplary compounds of Formula I were found to significantly enhance 24hour memory, in the object recognition assay. Control experiments showedthat compound administration did not significantly affect the cumulativedistance traveled or amount of time spent exploring the left and righthalves of the box. Significant effects were seen at severalconcentrations, depending on the compound, including concentrations of0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg.

Exemplary compounds were also found to enhance contextual memory in thefear conditioning assay. Significant effects were seen at severalconcentrations, depending on the compound, including 0.03 mg/kg, 0.1mg/kg, 0.3 mg/kg and 1.0 mg/kg.

Exemplary compounds were also found to reverse haloperidol-inducedcatalepsy. Significant effects were seen at several concentrations,depending on the compound, ranging from 0.01 to 1.0 mg/kg, p.o.

Biological Example 2 Effect of Exemplary Compounds on Cardiac Function

Exemplary compounds of the present invention are evaluated in severalmodels of cardiovascular function, including the telemeterized rat andBeagle dog. Each test compound (or vehicle) is administered by oralgavage, and animals are evaluated after each dose for any abnormalclinical signs. Hemodynamic (Heart rate, systolic, diastolic, and meanarterial pressure) and electrocardiographic parameters (PR interval, QRSduration, QT/QTc interval, RR interval) are recorded following dosing.

Results for Several Exemplary Compounds

Administration of several compounds of the present disclosure lead tochanges in blood pressure and increases in heart rate.)

It will be understood by one skilled in the art that the describedembodiments herein do not limit the scope of the invention. Thespecification, including the examples, is intended to be exemplary only,and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

What is claimed is: 1-134. (canceled)
 135. A pharmaceutical compositioncomprising: a pharmaceutically acceptable carrier; and a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, selectedfrom group consisting of:6-methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide;6-methyl-4-[(1-methylcyclopropyl)amino]-N-(1H-pyrrol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide;N-[(2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;andN-[(6-chloropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.136. The pharmaceutical composition of claim 135, wherein the compoundis6-methyl-4-[(1-methylcyclopropyl)amino]-N-(1H-pyrrol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide,or a pharmaceutically acceptable salt thereof.
 137. A pharmaceuticalcomposition comprising: a pharmaceutically acceptable carrier; and acompound of Formula (I), or a pharmaceutically acceptable salt thereof,selected from group consisting of:6-methyl-N-{[5-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;6-methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;6-methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrazin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide;6-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;and6-methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,3-oxazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide.138. The pharmaceutical composition of claim 137, wherein the compoundis6-methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide,or a pharmaceutically acceptable salt thereof.
 139. A pharmaceuticalcomposition comprising: a pharmaceutically acceptable carrier; and acompound of Formula (I), or a pharmaceutically acceptable salt thereof,selected from group consisting of:N-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;N-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;N-{[1-(3-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide;N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; andN-[(6-methoxy-2-methylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide.140. The pharmaceutical composition of claim 139, wherein the compoundis N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, or apharmaceutically acceptable salt thereof.
 141. A method of enhancingmemory in in a subject with a cognitive disorder, comprisingadministering to the subject an effective amount of a composition ofclaim
 135. 142. The method of claim 141, wherein the cognitive disorderis Parkinson’s disease.
 143. A method of enhancing memory in in asubject with a cognitive disorder, comprising administering to thesubject an effective amount of a composition of claim
 136. 144. Themethod of claim 143, wherein the cognitive disorder is Parkinson’sdisease.
 145. A method of enhancing memory in in a subject with acognitive disorder, comprising administering to the subject an effectiveamount of a composition of claim
 137. 146. The method of claim 145,wherein the cognitive disorder is Parkinson’s disease.
 147. A method ofenhancing memory in in a subject with a cognitive disorder, comprisingadministering to the subject an effective amount of a composition ofclaim
 138. 148. The method of claim 147, wherein the cognitive disorderis Parkinson’s disease.
 149. A method of enhancing memory in in asubject with a cognitive disorder, comprising administering to thesubject an effective amount of a composition of claim
 139. 150. Themethod of claim 149, wherein the cognitive disorder is Parkinson’sdisease.
 151. A method of enhancing memory in in a subject with acognitive disorder, comprising administering to the subject an effectiveamount of a composition of claim
 140. 152. The method of claim 151,wherein the cognitive disorder is Parkinson’s disease.
 153. A method oftreating a cognitive impairment in in a subject with Parkinson’sdisease, comprising administering to the subject an effective amount ofa composition of claim
 136. 154. A method of treating a cognitiveimpairment in in a subject with Parkinson’s disease, comprisingadministering to the subject an effective amount of a composition ofclaim 137.